Oximes of 4-benzoyl-piperidines

ABSTRACT

Novel 3-(4-piperidyl)-1,2-benzisoxazoles, intermediates and processes for the preparation thereof, and methods for alleviating pain utilizing compounds or compositions thereof are disclosed.

This is a division, of application Ser. No. 319,871 filed Nov. 12, 1981now U.S. Pat. No. 4,355,037.

The present invention relates to novel3-(4-piperidyl)-1,2-benzisoxazoles. More particularly, the presentinvention relates to 3-(4-piperidyl)-1,2-benzisoxazoles of formula 1##STR1## wherein R is hydrogen, loweralkyl, loweralkenyl,cycloalkylloweralkyl, phenylloweralkyl, hydroxy,diloweralkylaminoloweralkyl, cyano, cyanomethyl, ##STR2## or a group ofthe formula ##STR3## wherein R¹ is hydrogen, loweralkyl or a group ofthe formula OR² wherein R² is phenyl or benzyl; X is hydrogen,loweralkyl, loweralkoxy, halogen or hydroxy; m is 1 or 2; thegeometrical isomers and optical antipodes thereof; or thepharmaceutically acceptable acid addition thereof, which are useful asanalgetic agents, alone or in combination with inert pain-alleviatingadjuvants.

Preferred 3-(4-piperidyl)-1,2-benzisoxazoles of the present inventionare those compounds wherein R is hydrogen, lowerlalkyl, loweralkenyl orcycloalkylloweralkyl. Most preferred 3-(4-piperidyl)-1,2-benzisoxazolesof the present invention are those compounds wherein R is loweralkenylor cycloalkylloweralkyl.

Subgeneric to 3-(4-piperidyl)-1,2-benzisoxazoles of the presentinvention are compounds wherein:

(a) R is phenylloweralkyl;

(b) R is hydroxy or ##STR4##

(c) R is diloweralkylaminoalkyl;

(d) R is cyano or cyanomethyl; and

(e) R is a group of the formula ##STR5## wherein R¹ is hydrogen,loweralkyl or a group of the formula OR² wherein R² is phenyl or benzyl.

The present invention also relates to benzoylpiperidines of formula 2##STR6## wherein R is hydrogen, loweralkyl, benzyl or a group of theformula ##STR7## wherein R¹ is hydrogen, loweralkyl or a group of theformula OR² wherein R² is benzyl; X is hydrogen, loweralkyl,loweralkoxy, halogen or hydroxy; Z is halogen or hydroxy; m is 1 or 2;the optical antipodes thereof; or salts thereof when R is hydrogen,loweralkyl or benzyl, and to benzoylpiperidine oximes and O-derivativesthereof of formula 3 ##STR8## wherein R is hydrogen, loweralkyl,loweralkenyl or a group of the formula ##STR9## wherein R¹ is hydrogen,loweralkyl or a group of the formula OR² wherein R² is benzyl; R³ ishydrogen or a group of the formula ##STR10## wherein R⁴ is hydrogen orloweralkyl; X is hydrogen, loweralkoxy, loweralkyl, halogen or hydroxy;Z is halogen or hydroxy m is 1 or 2; the geometric isomers and opticalantipodes thereof; or salts thereof when R is hydrogen, loweralkyl orloweralkenyl; useful as intermediates for the preparation of thehereinbefore mentioned 3-(4-piperidyl)-1,2-benzisoxazoles.

As used through the specification and appended claims, the term "alkyl"refers to a straight or branched chain hydrocarbon radical containing nounsaturation and having 1 to 10 carbon atoms such as methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl, 4-heptyl,2-octyl, 3-nonyl, 4-decyl and the like; the term "alkenyl" refers to astraight or branched chain hydrocarbon radical containing unsaturationin the form of a single carbon to carbon double bond and having from 3to 10 carbon atoms such as propenyl, 2-butenyl, 2-methyl-2-butenyl,3-hexenyl, 3-ethyl-2-pentenyl, 3-methyl-3-heptenyl, nonenyl, decenyl,and the like; the term "cycloalklyl" refers to a saturated hydrocarbongroup possessing at least one carbocyclic ring, the ring containing from3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and the like; the term "alkoxy" refers to amonovalent substituent which consists of an alkyl group linked throughan ether oxygen and having its free valence bond from the ether oxygensuch as methoxy, ethoxy, propoxy, butoxy, 1,1-dimethylethoxy, pentoxy,3-methylpentoxy, 2-ethylpentoxy, 2-methyloctoxy, octoxy, decoxy and thelike; the term "alkanol" refers to a compound formed by a combination ofan alkyl group and hydroxy radical. Examples of alkanols are methanol,ethanol, 1- and 2-propanol, 2,2-dimethylethanol, hexanol, octanol,decanol and the like. The term "alkanoic acid" refers to a compoundformed by combination of a carboxyl group with a hydrogen atom or alkylgroup. Examples of alkanoic acids are formic acid, acetic acid,propanoic acid, 2,2-dimethylacetic acid, hexanoic acid, octanoic acid,decanoic acid and the like; the term "halogen" refers to a member of thefamily fluorine, chlorine, bromine or iodine. The term "alkanoyl" refersto the radical formed by removal of the hydroxyl function from analkanoic acid. Examples of alkanoyl groups are formyl, acetyl,propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl, decanoyl and thelike. The term "lower" as applied to any of the aforementioned groupsrefers to a group having a carbon skeleton containing up to andincluding 7 carbon atoms.

The compounds of the present invention which lack an element of symmetryexist as optical antipodes and as the racemic forms thereof. The opticalantipode may be prepared from the corresponding racemic forms bystandard optical resolution techniques, involving, for example, theseparation of diasteromeric salts of those instant compoundscharacterized by the presence of a basic amino group and an opticallyactive acid, or by the synthesis from optically active precursors.

The benzoylpiperidine oximes and O-derivatives of formula 3 thereofexist in isomeric Z- and E-forms. For example,1-acetyl-4-(4,5-dimethoxy-2-hydroxy)piperidine oxime exists in the Z-and E-isomeric forms, 4 and 5, respectively, as shown below: ##STR11##In the Z-isomer, the hydroxyl group of the oxime function and thedimethoxyphenol moiety, the group of greater priority, are cis to eachother and in E-isomer, the hydroxyl group of the oxime function and thedimethoxyphenol moiety, are trans to each other. The wiggly ( ) line inthe formulas of the oximes and O-derivatives thereof of formula 3indicate that the compound may be the E- or Z-isomer. See B. Unterhalt,Method Chim. 6, 403 (1975), for a discussion of the E-Z nomenclature.

The present invention comprehends all optical isomers and racemic formsthereof and all geometric isomers of the compounds disclosed and claimedherein. The formulas of the compounds shown herein are intended toencompass all possible geometric and optical isomers of the compounds sodepicted.

The novel 3-(4-piperdyl)-1,2-benzisoxazoles 1 of the present inventionare synthesized by the processes illustrated in Reaction Schemes A to E.

To prepare the parent system, namely the3-(4-piperidyl)-1,2-benzisoxazole system, the amino function ofcommercially available isonipecotic acid (hexahydropyridine-4-carboxylicacid) is protected by acylation to an N-alkanoyl derivative 8 which iscondensed with an alkoxy- or halobenzene 10 to form a4-benzoylpiperidine 11 via a carboxylic acid halide 9. A4-benzoylpiperidine 11, so obtained, is subsequently cyclized to a3-(1-alkanoyl-4-piperidyl)-1,2-benzisoxazole 17 which is hydrolyzed to a3-(1-unsubstituted-4-piperidyl)-1,2-benzisoxazole 18. See Schemes A andB.

The 3-(4-piperidyl)-1,2-benzisoxazole system having an alkyl group atthe 1-position of the piperidyl ring is prepared by condensing a4-chloro-N-alkylpiperidine 19 with a benzonitrile 20 and cyclizing the4-benzoyl-N-alkylpiperidine 21, so obtained, to a3-(1-alkyl-4-piperidyl)-1,2-benzisoxazole 18. See Scheme C.

The acylation of isonepecotic acid 6 to its N-alkanoyl derivative 8 isperformed by treating the secondary amine 6 with an anhydride 7 bymethods well-known in the art. For example, treatment of isonepecoticacid 6 with acetic anhydride, in the presence or absence of a co-solventsuch as acetic acid, at ambient temperature yields 8 where R⁵ is methyl.To prepare the N-formyl derivative 8, wherein R⁵ is hydrogen,acetic-formic acid anhydride, prepared from acetic anhydride and formicacid, is employed. In this case, it is preferable to utilize the mixedanhydride, acetic-formic acid anhydride, in situ and a slightly reducedtemperature within the range of about 0° to about 25° C.

The conversion of a piperidine-4-carboxylic acid 8 to apiperidine-4-carboxylic acid halide 9 is also performed by conventionalmethods. For example, N-acetylisonipecotic acid (8, R⁵ is methyl) istreated with thionyl chloride or thionyl bromide, in the presence orabsence of a halocarbon solvent such as dichloromethane, chloroform,dichloroethane and the like, or a mixture thereof, at a temperaturewithin the range of about ambient temperature to about 75° C. Thionylchloride is the preferred reagent. Dichloroethane and 65° C. are thepreferred solvent and reaction temperature, respectively. For thepreparation of the carboxylic acid chloride of N-formylisonipecoticacid, catalytic amounts of acetic anhydride may be employed.

The condensation of a piperidine-4-carboxylic acid halide 9 with analkoxyl- or halobenzene 10 is accomplished by treating a slurry of theacid halide 9 and benzene derivative 10 with a Friedel-Crafts catalystat about ambient temperature and heating the mixture to a temperature ofabout 50° to 150° C. to promote the reaction. Friedel-Crafts catalystsinclude aluminum chloride, ferric chloride, stannic chloride and thelike. Aluminum chloride is preferred. The reaction temperature is notnarrowly constant. However, a temperature of about 70° to 120° C. ispreferred.

The condensation of a piperidine carboxylic acid 8 with an alkoxy- orhalobenzene 10 is also accomplished by preparing a carboxylic acidhalide 9 as hereinbefore described and, without isolation of the halide9, treating the reaction mixture with the benzene component 10 and aFriedel-Crafts catalyst such as aluminum chloride, ferric chloride,stannic chloride and the like, at ambient temperature, and heating thereaction system at the reflux temperature thereof. Aluminum chloride isalso the preferred Friedel-Crafts catalyst in the direct process.

The cyclization of a 1-alkanoyl-4-benzoylpiperidine 11, wherein Z ishydroxyl, to a 3-(1-alkanoyl-4-piperidyl)-1,2-benzisoxazole 17 iseffected by first converting the benzoylpiperidine 11 to its oximederivative 15, 0-acylating the oxime derivative 15, and finally treatingthe 0-alkanoyloxime 16, so obtained, with a base.

The formation of an oxime 15 and its conversion to an 9-alkanoylderivative 16 proceeds readily by methods well-known in the art. Forexample, treatment of a benzoylpiperidine 11 with hydroxylaminehydrochloride and ammonium acetate as an acid scavenger in anaqueous-alkanol such as aqueous ethanol at about the reflux temperatureof the reaction mixture affords oxime 15, which is 0-acylated by meansof anhydrides such as formic anhydride, acetic anhydride and the like,or mixed anhydrides such as formic-acetic acid anhydride and the like,at reduced temperatures of about 0° C. to slightly elevated temperaturesof about 75° C. in the presence or absence of a co-solvent. When aco-solvent, for example, a halocarbon such as dichloromethane, isemployed, it is preferred to conduct the acylation at about ambienttemperature. In the absence of a co-solvent, it is preferred to performthe reaction at about 60° C. When a mixed anhydride such asacetic-formic acid anhydride is used as the acylating agent, it ispreferred to carry out the reaction in the absence of a co-solvent at aslightly reduced temperature within the range of about 0° to 20° C.

The elaboration of a 1,2-benzisoxazole 17 from an 0-acyloxime 16proceeds conveniently in the presence of a base, as hereinbeforeindicated. Suitable bases include alkali and alkaline earth carbonatesand bicarbonates such as potassium and magnesium carbonates, and sodiumand calcium bicarbonates, and alkali and alkaline earth hydrides such aslithium, sodium, potassium or calcium hydrides. A solvent is employed tofaciliate the cyclization. Among suitable solvents, there may bementioned alkanols, i.e., methanol, ethanol, 2-propanol and the like,and polar aprotic substances such as dimethylacetamide,dimethylformamide and hexamethylphosphoramide, alone or admixed with anethereal co-solvent such as diethylether, dimethoxyethane, dioxane ortetrahydrofuran. Generally, an alkanol is used as the solvent, when analkali or alkaline earth carbonate or bicarbonate is employed as thebase, and an aprotic polar substance is used as the solvent when analkali or alkaline earth hydride is utilized as the base. Potassiumcarbonate in methanol and sodium hydride in dimethylformamide are thepreferred cyclization reagents.

The temperature of the cyclization reaction is not critical. Usually,however, it is preferred to carry out the cyclization at the refluxtemperature of the reaction mixture when an alkali or alkaline earthcarbonate or bicarbonate is used, and at about ambient temperature toabout 90° C., when an alkali or alkaline earth hydride is employed. Inthe case of the latter, a cyclization temperature of about ambienttemperature is preferred.

The hydrolysis of a 3-(1-alkanoyl-4-piperidyl)-1,2-benzisoxazole 13 to a3-(1-unsubstituted-4-piperidyl)-1,2-benzisoxazole 17 is conducted bymethods known per se involving a mineral acid such as hydrochloric acid,hydrobromic acid and the like, at a reaction temperature between aboutambient temperature and the reflux temperature of the hydrolysismixture. Hydrochloric acid at the reflux temperature is preferred. Whenhydrobromic acid, e.g., 48% hydrobromic acid, is employed, aromaticalkoxy groups, i.e., anisole moieties, are cleaved to hydroxyl groups,i.e., phenolic moieties.

The condensation of a 4-chloro-N-alkylpiperidine 19 with a benzonitrile20 is effected by conventional Grignard techniques. Typically, thechloropiperidine 19 is dissolved or suspended in an ethereal solventsuch as tetrahydrofuran; magnesium is added and the mixture is heatedunder reflux until the reaction is complete. An initiator such as ethylbromide may be employed to facilitate the reaction.

The cyclization of a 1-alkyl-4-benzoylpiperidine 21 to a3-(1-alkyl-4-piperidyl)-1,2-benzisoxazole 22 is performed by treatingthe benzoylpiperidine 21 with hydroxylamine as a salt thereof with abase in a suitable solvent. Among salts of hydroxylamine, there may bementioned the hydrochloride, hydrobromide and sulfate, the hydrochloridebeing preferred. Bases include alkali metal hydroxides such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, and the like, andalkaline like, and alkaline earth hydroxides such as calcium hydroxide,magnesium hydroxide and the like. The cyclization temperature is notcritical. To promote the reaction, however, it is desirable to heat thesystem under reflux. The intermediate oxime of 21 may be isolated, andis isolated in certain cases, and cyclized to 22. The cyclization isaccomplished with a hydride such as sodium or potassium hydride in amixture of a polar aprotic solvent such as dimethylacetamide,dimethylformamide or hexamethylphosphoramide and an ethereal solventsuch as tetrahydrofuran, dioxane or 1,2-dimethoxyethane at an elevatedtemperature of about 70° to 110° C. Sodium hydride intetrahydrofurandimethylformamide at a temperature of about 90° C. is thepreferred reaction condition.

A 3-(1-unsubstituted-4-piperidyl)-1,2-benzisoxazole 18 is also preparedby hydrolyzing a 1-alkanoyl-4-benzoylpiperidine 11 to a 1-unsubstituted4-benzoylpiperidine 12, acylating a 4-benzoylpiperidine 12 to abenzoyl-1-piperidine carboxylic acid phenyl methyl ester 13, cyclizing abenzoylpiperidine ester 13 to a benzisoxazolylpiperidine carboxylic acidester 25, and hydrolyzing an ester 25 to a 1-unsubstituted compound 18.See Schemes A and D.

The hydrolysis of a 1-alkanoyl-4-benzoylpiperidine 11 to a1-unsubstituted 4-benzoylpiperidine 12 is performed by methodswell-known in the art, involving, for example, treatment of an alkanoylderivative 11 with a mineral acid such as hydrochloric acid at elevatedtemperatures at or about the reflux temperature of the reaction mixture.

The acylation of a 1-unsubstituted benzoylpiperidine 12 is convenientlyaccomplished by treating the piperidine 12 with a benzyl haloformate,for example, benzyl chloroformate or benzyl bromoformate, in ahalocarbon such as dichloromethane, chloroform or the like, in thepresence of an acid scavenger such as an alkali carbonate or alkalibicarbonate such as potassium carbonate or sodium bicarbonate. Benzylchloroformate in dichloromethane containing sodium bicarbonate is thepreferred reagent system when Z is hydroxy. Stronger bases such ascarbonates are preferred when Z is halogen.

The cyclization of a benzoylpiperidine ester 13 to a benzisoxazole 25 iseffected by the processes hereinbefore described, preferrably, by thesequence involving the conversion of the ketone function to the oximeacylate thereof, and base treatment.

The hydrolysis of an ester 25 to a 1-unsubstituted 18 is conducted byart-known methods, involving the use of a hydrogen halide wuch ashydrogen chloride or hydrogen bromide in an alkanoic acid such as formicacid, acetic acid or propionic acid. Hydrogen bromide in acetic acid ispreferred.

Similarly, a 3-(1-unsubstituted-4-piperidyl-)1,2-benzisoxazole 18 may beprepared by benzylating a 1-unsubstituted 4-benzoylpiperidine 12 to a1-benzyl-4-benzoylpiperidine 14, cyclizing a benzoylpiperidine 14 to abenzisoxazole 26 and cleaving the 1-benzyl group of 26 to a1-unsubstituted compound 18.

The benzylation of a 1-unsubstituted piperidine 12 is performed by meansof a benzyl halide such as benzyl chloride or benzyl bromide, benzylbromide being preferred, in the presence of a base, suspended ordissolved in a polar aprotic solvent. Suitable bases include alkalicarbonates and bicarbonates, such as, for example, sodium and potassiumcarbonate, and sodium and potassium bicarbonate. Suitable polar aproticsolvents include dimethylacetamide, dimethylformamide andhexamethylphosphoramide. Sodium bicarbonate and dimethylformamide arethe preferred base and solvent.

Cyclization processes hereinbefore described, i.e., cyclizationprocesses 11→15, 16→17, and 21→22, may be employed to convert abenzylpiperidine 14 to benzisoxazole 26. The sequence involving the0-acyloxime may be preferred.

The cleavage of a 3-(1-benzyl-4-piperidyl)-1,2-benzisoxazole 26 to a1-unsubstituted compound 18, i.e., the debenzylation of 26, may beachieved by the dealkylation process described immediately below.

A 3-(1-unsubstituted-4-piperidyl)-1,2-benzylisoxazole 18 is prepared bydealkylation of a 3-(1-unsubstituted-4-piperidyl)-1,2-benzisoxazole 22as illustrated in Scheme C. The dealkylation is readily performed bytreating an alkylpiperidine 22 with a phenyl haloformate such as phenylchloroformate or phenyl bromoformate in an appropriate solvent in thepresence of a suitable base to afford a quaternary piperidinium salt 23,for example,4-(4-fluoro-1,2-benzisoxazole-3-yl)-1-methyl-1-phenoxycarbonylpiperidinium chloride, which without isolation, is transformed to apiperidine carboxylic acid phenyl ester 24 and hydrolyzed to1-unsubstituted compound 18.

Among suitable bases, there may be mentioned alkali and alkaline earthcarbonates and bicarbonates such as, for example, sodium and potassiumcarbonate and sodium and potassium bicarbonate, and calcium carbonateand bicarbonate. Potassium carbonate is preferred. Appropriate solventsinclude halocarbons such as dichloromethane, chloroform, dichloroethaneand the like, polar aprotic substances such as dimethylacetamide,dimethylformamide and hexamethylphosphoramide, and aromatics such asbenzene, toluene, xylene and the like. Aromatics are preferred; tolueneis most preferred. The reaction temperature is not critical. An elevatedtemperature is, however, desirable to promote the loss of the elementsof RU from the quaternary salt. The hydrolysis of a piperidinecarboxylic acid phenyl ester 24 to 1-unsubstituted piperidine 18 isperformed by conventional techniques employing alkali hydroxides such aspotassium hydroxide in an aqueous alkanol such as aqueous ethanol at thereflux temperature of the reaction system.

Derivatives of the parent system, i.e., derivatives of the3-(4-piperidiyl)-1,2-benzisoxazole system, are prepared from a nitrogenunsubstituted compound 18 by the processes outlined in Reaction SchemesE, F and G.

To prepare a 3-(1-alkenyl-4-piperidyl)-1,2-benzisoxazole 28, a3-(1-unsubstituted-4-piperidyl)-1,2-benzisoxazole 18 is contacted withan alkenyl halide 27 in a suitable solvent in the presence of an acidacceptor. Suitable solvents include polar aprotic substances such asdimethylacetamide, dimethylformamide and hexamethylphosphoramide.Suitable acid acceptors include alkali carbonates and alkalibicarbonates such as potassium carbonate and sodium bicarbonate.Potassium iodide and elevated temperatures within the range of 75°-100°C. may be employed to promote the alkenylation.

Alternatively, a 3-(1-alkenyl-4-piperidyl)-1,2-benzisoxazole 28 may beelaborated by alkenylation of oxime 29, prepared from a 1-unsubstitutedbenzoylpiperidine 12 by hereinbefore described methods, according toprocesses utilized for the conversion of piperidylbenzisoxazole 18 toN-alkenylpiperidylbenzisoxazole 28, followed by cyclization, also bytechniques disclosed herein.

To synthesize a 3-(1-phenylalkyl-4-piperidyl)-1,2-benzisoxazole 34 or a3-(1-cycloalkylalkyl-4-piperidyl)-1,2-benzisoxazole 31, the1-unsubstituted compound 18 is treated, respectively, with a phenylalkylhalide 32 or a cycloalkylalkyl halide 33 in a polar aprotic solvent suchas dimethylacetamide, dimethylformamide and hexamethylphosphoramide, inthe presence of an acid scavenger such as sodium or potassium carbonateor bicarbonate. A promotor such as potassium iodide may be used and thereaction may be conducted at an elevated temperature of 50°-100° C. tofacilitate the conversion. Potassium carbonate in dimethylformamide at60°-80° C. are the preferred reaction conditions.

To introduce the dialklaminoalkyl group into the 1-unsubstitutedpiperidylbenzisoxazole 18, i.e., to prepare a3-(1-dialkylaminoalkyl-4-piperidyl)-1,2-benzisoxazole 36, one treats apiperidylbenzisoxazole 18 with a dialkylaminoalkyl halide 35 in analkanol, for example, methanol, ethanol, 2-propanol, 1-butanol and thelike, n-butanol being preferred, in the presence of an acid acceptorsuch as an alkali carbonate (potassium carbonate) or bicarbonate (sodiumbicarbonate) as in similar akylations, a promotor such as potassiumiodide and elevated temperatures, for example, the reflux temperature ofthe reaction system may be used to facilitate the reaction.

To prepare a 3-(1-hydroxy-4-piperidyl)-1,2-benzisoxazole 38, a1-unsubstituted compound 18 is treated with benzoyl peroxide in anaromatic solvent such as benzene, toluene or xylene, benzene beingpreferred, in the presence of a base such as an alkali metal carbonateor bicarbonate, for example, potassium carbonate or sodium bicarbonate,potassium carbonate being preferred, to yield a3-(1-benzoyloxy-4-piperidyl)-1,2-benzisoxazole 37, which is hydrolyzedby methods known per se such as an alkali hydroxide (sodium hydroxide)in an aqueous alkanol (aqueous ethanol) to provide the 1-hydroxycompound 38. Neither the oxidation nor hydrolysis temperatures arenarrowly critical. At about ambient temperature, the oxidation proceedsat a reasonable rate, and at the reflux temperature of the reactionsystem, the hydrolysis also proceeds at a convenient rate.

To furnish a 3-(1-cyano-4-piperidyl)-1,2-benzisoxazole 43, (R¹³ isalkyl), a 3-(1-alkyl-4-piperidyl)-1,2-benzisoxazole 40 is treated with acyanogen halide such as cyanogen bromide 41 or cyanogen chloride,preferably cyanogen bromide, in a halocarbon such as dichloromethane,trichloromethane or dichloroethane, preferably dichloromethane, in thepresence of an acid scavenger such as sodium or potassium carbonate orsodium or potassium bicarbonate, preferrably potassium carbonate, toafford an alkylcyanopiperidinium salt 42, for example,5-methyl-1,2-benzisoxazol-3-yl)-1-cyano-1-methyl-piperidinium chloride,which loses the elements of an alkylhalide (R¹³ U) to form a 1-cyanoderivative 43. The reaction proceeds readily at moderate temperatures.To facilitate the conversion, however, elevated temperatures, i.e., thereflux temperatures of the system, are employed.

Alternatively, a 3-(1-unsubstituted-4-piperidyl)-1,2-benzisoxazole 40(R¹³ is hydrogen) is treated with a cyanogen halide 41 such as cyanogenbromide or cyanogen chloride, preferrably cyanogen bromide, to afford a1-cyano derivative 43. The conversion is performed in a halocarbon suchas dichloromethane trichlormethane or dichloroethane, preferrablytrichoromethane, in the presence of an acid acceptor such as sodium orpotassium carbonate, or sodium and potassium bicarbonate, preferrablysodium bicarbonate. A promoter such as potassium iodide may be employedto facilitate the conversion. At elevated temperature, for example, thereflux temperature of the system, may also be employed to assure areasonable rate of conversion.

A 3-(1-cyano-4-piperidyl)-1,2-benzisoxazole 43 may be hydrolyzed to a3-(1-unsubstituted-4-piperidyl)-1,2-benzisoxazole 40 (R¹³ is hydrogen)by conventional methods involving acidic or basic reaction conditions.See, for example, R. B. Wagner and Harry P. Zook, "Synthetic OrganicChemistry", John Wiley and Sons, Inc., New York, N.Y., page 680 and thereference cited therein.

To synthesize a 3-(1-cyanomethyl-4-piperidyl)-1,2-benzisoxazole 45, a1-unsubstituted piperidine 40 (R¹³ is hydrogen) is contacted with ahaloacetonitrile 44 such as chloro- or bromoacetonitrile, preferrablychloroacetonitrile, in a polar aprotic solvent such asdimethylformamide, dimethylacetamide or hexamethylphosphoramide,preferably dimethylformamide, in the presence of an acid acceptor suchas potassium or sodium bicarbonate or potassium or sodium carbonate,preferrably potassium carbonate, and a promotor such as potassiumiodide. To assure completion of the conversion, an elevated temperaturewithin the range of about 50° to 100° C. may be employed. A temperaturewithin the range of about 80° to 85° is preferred.

The 3-(4-piperidyl)-1,2-benzisoxazoles of the present invention areuseful as analgetics due to their ability to alleviate pain in mammals.The analgetic utility is demonstrated in the phenyl-p-quinone writhingassay in mice, a standard assay for analgesia [Proc. Soc. Exptl. BiolMed., 95 729 (1957)]. Thus, for instance, the subcutaneous doseeffecting an approximately 50% inhibition of writhing (ED₅₀) in miceproduced in this assay is as follows:

    ______________________________________                                                              ED.sub.50                                               Compound              mg/kg                                                   ______________________________________                                        3-(1-methyl-4-piperidyl)-                                                     1,2-benzisoxazole hydrochloride                                                                     0.415                                                   3-(4-piperidyl)-1,2-benzisoxazole                                             hydrochloride         0.517                                                   3-(1- -phenylethyl-4-piperidyl)-                                              1,2-benzisoxazole hydrochloride                                                                     0.386                                                   3-(1-allyl)-4-piperidyl)-1,2-                                                 benzisoxazole hydrochloride                                                                         1.06                                                    3-[1-(3-dimethylaminopropyl)-                                                 4-piperidyl]-1,2-benzisoxazole                                                difumarate            7.4                                                     3-(1-methyl-4-piperidyl)-5-                                                   methyl-1,2-benzisoxazole fumarate                                                                   0.566                                                   3-(4-piperidyl)-6-fluoro-1,2-                                                 benzisoxazole hydrochloride                                                                         1.79                                                    3-(4-piperidyl)-6-chloro-1,2-                                                 benzisoxazole hydrochloride                                                                         5.6                                                     3-1-(allyl-4-piperidyl)-6-fluoro-                                             1,2-benzisoxazole hydrochloride                                                                     0.455                                                   propoxyphene (standard)                                                                             3.9                                                     pentazocine (standard)                                                                              1.3                                                     ______________________________________                                    

Analgesia production is achieved when the present3-(4-piperidyl)-1,2-benzisoxazoles are administered to a subjectrequiring such treatment as an effective oral, parenteral or intravenousdose of from 0.01 to 100 mg/kg of body weight per day. A particularlyeffective amount is about 25 mg/kg of body weight per day. It is to beunderstood, however, that for any particular subject, specific dosageregimens should be adjusted according to the individual need and theprofessional judgement of the person administering or supervising theadministration of the aforesaid compound. It is to be further understoodthat the dosages set forth herein are exemplary only and that they donot, to any extent, limit the scope or practice of the invention.

Effective amounts of the present invention may be administered to asubject by any one of various methods, for example, orally as incapsules or tablets, parenterally in the form of sterile solutions orsuspensions, and in some cases intravenously in the form of sterilesolutions. The 3-(4-piperidyl)-1,2-benzisoxazoles of the presentinvention, while effective themselves, may be formulated andadministered in the form of their pharmaceutically acceptable additionsalts for purposes of stability, convenience or crystallization,increased solubility and the like.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid and thelike, and salts of tribasic carboxylic acids such as, for example,carboxysuccinic acid, citric acid and the like.

Effective quantities of the compounds of the invention may beadministered orally, for example, with an inert diluent or with anedible carrier. They may be enclosed in gelatin capsules or compressedinto tablets. For the purpose of oral therapeutic administration, theaforesaid compounds may be incorporated with excipient and used in theform of tablets, troches, capsules, elixirs, suspensions, syrups,wafers, chewing gums and the like. These preparations should contain atleast 0.5%) of active compound, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of active compound in such composition issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that anoral dosage unit form contains between 1.0-300 milligrams of the activecompound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragancanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotes; a glidant suchas colloida silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring may be added. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 50% of the weightthereof. The amount of active compounds in such compositions is suchthat a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes or multiple dose vialsmade of glass or plastic. ##STR12## Wherein R⁵ is hydrogen or alkyl; R⁶is alkyl; X is hydrogen, alkyl, alkoxy, halogen or hydroxy; Z ishydroxy; and m is 1 or 2. ##STR13## Wherein R⁷ is alkyl or alkanoyl; Uis halogen; X is hydrogen, alkyl, alkoxy, halogen or hydroxy; Z" ishalogen; and m is 1 or 2. ##STR14## Wherein X is hydrogen, alkyl,alkoxy, halogen or hydroxy; Z is halogen or hydroxy; and m is 1 or 2.##STR15## Wherein R⁸, R⁹ and R¹⁰ are each independently hydrogen oralkyl; U is halogen; X is hydrogen, alkyl, alkoxy, hydroxy or halogen; Zis halogen or hydroxy; and m is 1 or 2. ##STR16## Wherein R¹¹ and R¹²are each independently alkyl; U is halogen; X is hydrogen, alkyl,alkoxy, halogen and hydroxy; m is 1 or 2; n is 1 or 2; p is 0 to 4; andq is 1 or 2. ##STR17## Wherein R¹³ is hydrogen or alkyl; U is halogen;and X is hydrogen, alkyl, alkoxy, halogen or hydroxy.

The following examples are for illustrative purposes only and are not tobe construed as limiting the invention. All temperatures are given isdegrees centrigrade (°C.).

EXAMPLE 1 1-Methyl-4-(2-chloro-5-methylbenzoyl)piperidine fumarate

To a suspension of 10.8 g of magnesium in 30 ml of anhydroustetrahydrofuran was added a crystal of iodine followed by a few mls of4-chloro-N-methylpiperidine. The reaction was initiated with a hot airgun and 54.3 g of 4-chloro-N-methylpiperidine in 100 ml of anhydroustetrahydrofuran was added dropwise at a rate maintaining reflux. Uponcompletion of the addition, the reaction mixture was refluxed for 3 hrsand then 50 g of 2-chloro-5-methylbenzonitrile in 225 ml oftetrahydrofuran was added dropwise. Upon completion of the addition, thereaction mixture was heated under reflux for an additional 2 hrs andstirred overnight at room temperature. The reaction mixture was pouredinto a solution of 100 g of ammonium chloride in 1 l of water, heated ona steam bath for 2 hrs, cooled, extracted with ether and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureand the residue was distilled (0.2 mm, 115°-125°) to give 54 g (56%) ofproduct. The fumerate salt was made by dissolving 1 g of product inapproximately 5 ml of acetonitrile and adding 0.5 g of fumaric acid. Thesuspension was stirred for 1 hr, filtered and the filter cake wasrecrystallized twice from ethanol-ether to give the salt, mp, 148°-150°.

Analysis: Calculated for C₁₄ H₁₈ ClNO C₄ H₄ O₄ : 58.77%C, 6.03%H,3.81%N. Found: 58.57%C, 5.89%H, 3.82%N.

EXAMPLE 2 4-(2,4-Difluorobenzoyl)-N-formylpiperidine

a. To the mixed anhydride of formic acid and acetic acid, prepared bydropping 334 ml of formic acid (98%) into 666 ml of acetic anhydride,over 15 mins at 20°, removing the ice bath and allowing the reactionmixture to warm up to 55°-60° and after 30 mins, cooling this reactionmixture to 15°, was added, over 5 mins, with stirring and cooling in anice bath, 129 g of isonipecotic acid. After stirring in an ice bath for16 hrs, the reaction mixture was distilled under vacuum at 80° untilcrystals formed. The residue was diluted with 1 l of isopropyl ether.The precipitate was collected, washed twice with 400 ml isopropyl etherand dried over potassium hydroxide under vacuum. Recrystallization fromisopropyl ether gave 120 g (76.3%) of N-formylisonipec-otic acid, mp,140°.

b. To 100 ml of freshly distilled thionyl chloride was added 30 g ofN-formylisonipecotic acid at 0°. After the addition was complete, 2 mlof acetic anhydride was added and the solution was stirred at 20° forthree hrs. The reaction mixture was diluted with 3 400-ml portions ofpetroleum ether, bp, 60°-80°. The resulting solid was collected, washedwith 50 ml of ether and dried under vacuum over phosphorous pentoxide toyield 33.5 g (100%) of N-formylisonipecotic acid chloride.

c. To a slurry of 39 g of aluminum chloride and 120 ml of1,3-difluorobenzene was added dropwise, with stirring, 30 g ofN-formylisonipecotic acid chloride. The reaction mixture was stirredunder reflux for two hrs and poured into 1 l of ice-water. The mixturewas extracted with 4 350-ml portions of chloroform. The combined organicextracts were washed with 2 300-ml portions of water, dried, filteredand evaporated. Trituration with petroleum ether and washing with etherat 0°, yielded 14 g (32.3%) of product, mp, 75°.

Analysis: Calculated for C₁₃ H₁₃ F₂ NO₂ : 61.63%C, 5.17%H, 5.53%N.Found: 61.42%C, 5.07%H, 5.42%N.

EXAMPLE 3 1-Acetyl-4-(2-hydroxy-5-methoxybenzoyl)piperidine

To a stirred mixture of 60.0 g of isonipecotic acid and 290 ml of1,2-dichloromethane, at 40°, was added dropwise, 27 ml of thionylchloride, dissolved in 27 ml of dichloroethane. After 50% of the thionylchloride had been added, the temperature was raised to 65°. Aftercomplete addition of the thionyl chloride, the reaction mixture wasstirred at 65° for 1 hr. The reaction mixture was cooled to 20° and 48.6g of 1,4-dimethoxybenzene was added, followed by the slow addition of93.6 g of aluminum chloride. The solution was heated under reflux for 4hrs, the dichloroethane was decanted from the insoluble complex, andconcentrated hydrochloric acid was added. The acid hydrolysate was addedto the dichloroethane solution and the mixture was extracted three timeswith chloroform. The organic extract was washed with water, dried overanhydrous magnesium sulfate and the solvent was removed in vacuo togiave an oil. The oil was scratched with a glass rod untilcrystallization was effected. The solid was collected to yield 87.0 g ofproduct. Recrystallization twice from isopropyl ether gave ananalytically pure product, mp, 93°-94°.

Analysis: Calculated for C₁₅ H₁₉ NO₄ : 64.96%C, 6.91%H, 5.05%N. Found:64.91%C, 6.90%H, 5.00%N.

EXAMPLE 4 1-Acetyl-4-(2,4-difluorobenzoyl)piperidine

To a slurry of 6.6 g of aluminum chloride and 20 ml of1,3-difluorobenzene was added, with stirring at ambient temperature, 5.0g of N-acetylisonipecotyl chloride. The reaction mixture was heatedunder reflux for 11/2 hrs and then poured onto 100 ml of ice and water.The mixture was extracted with chloroform. The chloroform fractions werecombined, washed with water and dried over anhydrous magnesium sulfateand filtered. Evaporation of the filtrate gave an oil. Trituration ofthe oil with pentane gave 4.65 g (65.9%) of product, mp, 100°-102°.

Analysis: Calculated for C₁₄ H₁₅ F₂ NO₂ : 62.91%C, 5.66%H, 5.24%N.Found: 62.82%C, 5.43%H, 5.21%N.

EXAMPLE 5 1-Acetyl-4-(2-hydroxy-4,5-dimethoxybenzoyl)piperidine

To a stirred mixture of 20.0 g of isonipecotic acid and 90 ml of1,2-dichloroethane at 40°, was added dropwise 9 ml of thionyl chloride,dissolved in 10 ml of dichloromethane. After 50% of the thionyl chloridehad been added, the temperature was raised to 60° for 1 hr. The reactionmixture was cooled to ambient temperature and 19.6 g of1,2,4-trimethoxybenzene was added, followed by the slow addition of 31.2g of aluminum chloride. The reaction mixture was refluxed for 4 hrs, thedichloroethane decanted from the insoluble complex and concentratedhydrochloric acid was added. The acid hydrolsate was added to thepreviously decanted dichloroethane and the mixture was extracted withdichloromethane. The solvent was removed in vacuo to give a solid whichrecrystallized from isopropanol to yield 19.7 g (54.&%) of product, mp,162°-164°.

Analysis: Calculated for C₁₆ H₂₁ NO₅ : 62.52%C, 6.89%H, 4.56%N. Found:62.47%C, 6.87%H, 4.55%N.

EXAMPLE 6 1-Acetyl-4-(5-fluoro-2-hydroxybenzoyl)piperidine

To a stirred mixture of 20.0 g of 1-acetylisonipecotic acid and 90 ml of1,2-dichloroethane, at 40°, was added dropwise, 27 ml of thionylchloride, dissolved in 9 ml of dichloroethane. After 50% of the thionylchloride had been added, the temperature was raised to 65°. Aftercomplete addition of the thionyl chloride, the reaction mixture wasstirred at 65° for 1 hr. After cooling to ambient temperature, 14.8 g of4-fluoroanisole was added, followed by the slow addition of 31.2 g ofaluminum chloride. The solution was heated under reflux for 4 hrs andthen poured into ice-water. The mixture was extracted two times withchloroform. The extract was washed with water, dried over anhydrousmagnesium sulfate and the solvent was removed in vacuo to give a solid.The solid was triturated with ether and recrystallized fromtoluene-cyclohexane to afford 16.5 g (53%) of product, mp, 121°-123°. Ananalytical sample was obtained by recrystallization fromtoluene-cyclohexane, mp, 121°-123°.

Analysis: Calculated for C₁₄ H₁₆ FNO₃ : 63.38%C, 6.08%H, 5.28%N. Found:63.20%C, 6.01%H, 5.11%N.

EXAMPLE 7 1-Acetyl-4-(2,4-dichlorobenzoyl)piperidine

To a stirred slurry of 25 g of aluminum chloride in 147 g of1,3-dichlorobenzene was added 18.97 g of N-acetylisonipecotyl chloride.The reaction mixture was heated to ca. 70°. Thereafter the reactionmixture was heated at ca. 120° for 2.5 hrs, with stirring. Unreacteddichlorobenzene was distilled in vacuum at 70° (16 mm). The residue wasdecomposed with 1 l of ice-water and 10 ml concentrated hydrochloricacid. The oil was isolated by decantation, washed twice with ca. 300 mlof water and dissolved in 300 ml of dichloromethane. The dichloromethaneextract was washed with 200 ml of water, with 100 ml of 2 N sodiumhydroxide solution, two times with 200 ml water and dried over anhydrousmagnesium sulfate. The dichloromethane was distilled to yield 16.2 g(54.0%) of product. An analytical sample was prepared by dissolving theoil in dichloromethane, treating with charcoal, filtering and eluatingwith dichloromethane from a column of aluminum oxide (Woelm, neutral,act. st. II) and removing the solvent.

Analysis: Calculated for C₁₄ H₁₅ C₁₂ NO₂ : 55.99%C, 5.04%H, 4.66%N,23.62%Cl. Found: 55.70%C, 5.03%H, 4.58%N, 23.70%Cl.

EXAMPLE 8 4-(2,4-Difluorobenzoyl)piperidine fumarate

A 3.0 g sample of 1-acetyl-4-(2,4-dichlorobenzoyl)piperidine in 20 ml of6 N hydrochloric acid was stirred for 3 hrs at 130°. The reactionmixture was cooled, extracted with ether and the acidic solution wasbasified with 25% sodium hydroxide solution. The basic solution wasextracted with dichloromethane filtrate and the combined extracts weredried over anhydrous magnesium sulfate. The mixture was filtered andthen evaporated to an oil which was converted to the fumarate salt.Yield 1.30 g (34.0%), mp 190°-192°.

Analysis: Calculated for C₁₂ H₁₃ F₂ NOC₄ H₄ O₄ : 56.30%C, 5.02%H,4.10%N. 56.23%C, 5.04%H, 4.09%N.

EXAMPLE 9 4-(2-Hydroxy-4-methoxybenzoyl)piperidine hydrochloride

To a round-bottom flask, equipped with a condenser and mechanicalstirrer, was added 25.0 g of1-acetyl-4-(2-hydroxy-4-methoxybenzoyl)piperidine and 148 ml of 6 Nhydrochloric acid. The reaction mixture was stirred under reflux for 6hrs and overnight at ambient temperature. The precipitate was collected,washed with acetone and recrystallized twice from ethanol to yield 16.70g of product, mp, 264°-266°.

Analysis: Calculated for C₁₃ H₁₇ O₃ N HCl: 57.47%C, 6.65%H, 5.16%N.Found: 57.26%C, 6.71%H, 5.06%N.

EXAMPLE 10 4-(2-Hydroxy-5-methoxybenzoyl)piperidine hydrobromide

A mixture of 10.0 g of1-acetyl-4-(2-hydroxy-5-methoxybenzoyl)-piperidine and 60 ml of 6 Nhydrochloric acid was heated under reflux for 6 hrs. The solution wasmade basic with ammonium hydroxide and extracted with dichloromethane.Evaporation of the dichloromethane in vacuo yielded 8.2 g of an oil. A3.5 g sample of the oil was converted to the hydrobromide salt bydissolving the oil in anhydrous ethanol and adding saturated hydrogenbromide-ether solution. The salt was recrystallized from ethanol-etherto yield 2.8 g (59.5%) of product as the hydrobromide, mp, 247°-249°.

Analysis: Calculated for C₁₃ H₁₇ NO₃ HBr: 49.38%C, 5.74%H, 4.43%N.Found: 49.93%C, 4.84%H, 4.45%N.

EXAMPLE 11 4-(2,4-Dichlorobenzoyl)piperidine hydrochloride

A solution of 4-(2,4-dichlorobenzoyl)-N-acetylpiperidine in 300 ml of 6N hydrochloric acid was heated under reflux for 4 hrs. The solution wascooled in an ice bath and basified with 25% sodium hydroxide. The basicsolution was extracted with 300 ml of dichloromethane. The organic phasewas washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo to give 31.6 g of solid. A 6.0 g sample of thesolid was dissolved in 100 ml of ethanol, with cooling in an ice bath.To the cold solution was added dropwise 10 ml of ether saturated withhydrogen chloride. The salt was collected and washed with ether andrecrystallized 2 times from a 2:1 ethanol-ether to afford 2.2 g (32%) ofproduct as the hydrochloride, mp, 215°-217°.

Analysis: Calculated for C₁₂ H₁₃ C₁₂ NO HCl: 48.92%C, 4.79%H, 4.75%N.Found: 49.01%C, 4.80%H, 4.65%N.

EXAMPLE 12 4-(2-Hydroxy-4-methoxybenzoyl)-1-piperidine carboxylic acid,phenylmethyl ester

To a stirred, ice-cooled mixture of 36.1 g of4-(2-hydroxy-4-methoxybenzoyl)piperidine, 16.3 g of sodium bicarbonateand 350 ml of dichloromethane, was added dropwise 22.9 ml of benzylchloroformate in dichloromethane. After the addition was complete, themixture was stirred at ambient temperature for 1.5 hrs, filtered and thefiltrate concentrated to an oil. The oil crystallized. The crystals werecollected, washed with hexane and dried to yield 42.4 g (76.5%) ofproduct. Recrystallization from isopropanol gave the analytical sample,mp, 89°-91°.

Analysis: Calculated for C₂₁ H₂₃ NO₅ : 68.28%C, 6.28%H, 3.79%N. Found:68.23%C, 6.30%H, 3.71%N.

EXAMPLE 13 1-Benzyl-4-(2-hydroxy-4-methoxybenzoyl)piperidine

A mixture of 14.50 g of 4-(2-hydroxy-4-methoxybenzoyl)piperidine, 6.40ml of benzyl bromide, 10.20 g of sodium bicarbonate and 74.0 ml ofdimethylformamide was stirred at 60° for 15 hrs. The reaction mixturewas poured into 250 ml of water and a precipitate formed. Theprecipitate was collected, washed with water and recrystallized fromethanol to yield 10.0 g (57.4%) of product, mp, 123°-125°.

Analysis: Calculated for C₂₀ H₂₃ NO₃ : 73.84%C, 7.08%H, 4.31%N. Found:73.76%C, 7.14%H, 4.26%N.

EXAMPLE 14 1-Methyl-4-(2,6-difluorobenzoyl)piperidine

A 6.60 g sample of magnesium was added to a 3-neck, round-bottom flaskequipped with a condenser, mechanical stirrer and addition funnel. Theapparatus was flame dried and cooled under a stream of nitrogen. About 1ml of ethyl bromide was dissolved in 30 ml of tetrahydrofuran and addedto the magnesium. The mixture was heated to reflux and 30.0 g of4-chloro-N-methylpiperidine, dissolved in 75 ml of tetrahydrofuran, wasadded. The addition was made at such a rate to achieve a modern reflux.After the addition was complete, the reaction mixture was heated underreflux for 1 hr. The reaction mixture was cooled to 0° and 31.4 g of2,6-difluorobenzonitrile, dissolved in 100 ml of tetrahydrofuran, wasadded dropwise through the addition funnel. After the addition wascomplete, the mixture was warmed to 40° for 3 hrs. The mixture waspoured into 1000 ml of ice-water, containing 65 g of ammonium chloride.The mixture was heated on a steam bath for 2 hrs and extracted withether. The ether extract was washed with saturated sodium bicarbonate,dried over anhydrous magnesium sulfate and the solvent was removed invacuo to yield an oil. The oil was purified by high pressure liquidchromatography (7% methanol in acetone) to yield the desired ketone(9.00 g, 17%) as an oil. The oil was dissolved in ether and a dilutesolution of oxalic acid/ether was added. The salt was collected, washedwith ether and recrystallized two times from ethyl acetate to yieldproduct as the oxalate, mp, 160°-162°.

Analysis: Calculated for C₁₃ H₁₅ F₂ NO HO₂ CCO₂ H: 54.68%C, 4.86%H,4.25%N. Found: 55.06%C, 5.12%H, 4.60%N.

EXAMPLE 15 4-(2,4-Difluorobenzoyl)-1-formylpiperidine oxime

A solution of 12 g of ammonium acetate in 45 ml of water was added to asolution of 15 g of 4-(2,4-difluorobenzoyl)-1-formylpiperidine and 6 gof hydroxylamine hydrochloride in 35 ml of ethanol. The mixture washeated for 18 hrs. at 90°, with stirring. The solvent was evaporated invacuum until precipitation occurred. Water (500 ml) was added. Themixture was filtered, washed with 300 ml of water and dried in vacuumover phosphorous pentoxide to yield 12 g (75.5%) of product.Recrystallization from ethanol and water yielded the analytical sample,mp, 185°.

Analysis: Calculated for C₁₃ H₁₄ F₂ N₂ O₂ : 58.18%C, 5.26%H, 10.44%N.Found: 58.40%C, 4.99%H, 10.43%N.

EXAMPLE 16 1-Acetyl-4-(2-hydroxy-5-methoxybenzoyl)piperidine oxime

A solution of 15.5 g of1-acetyl-4-(2-hydroxy-5-methoxybenzoyl)-piperidine, 7.0 g ofhydroxylamine hydrochloride, 9.5 g of ammonium acetate and 75 ml ofwater was heated under reflux for 20 hrs. The solution was poured intowater and extracted with dichloromethane. The dichloromethane extractwas washed with water, dried over anhydrous magnesium sulfate and thesolvent was removed in vacuo to give an oil. The oil was triturated withhot toluene. The toluene was decanted and the oil was triturated withether to give a solid. The tolulene triturant, upon standing, yielded asolid. The solids were combined and recrystallized from acetonitrile toyield 2.8 g (17.4%) of product, mp, 191°-193°, as a mixture of E- andZ-isomers. The chromatogram showed 2 spots.

Analysis: Calculated for C₁₅ H₂₀ N₂ O₄ : 61.65%C, 6.90%H, 9.59%N. Found:61.44%C, 6.76%H, 9.57%N.

EXAMPLE 17 1-Acetyl-4-(4,5-dimethoxy-2-hydroxy)piperidine oxime

A mixture of 14.0 g of 1-acetyl-4-(2-hydroxy-4,5-dimethoxyl)-piperidine,5.6 g of hydroxylamine hydrochloride, 7.6 g of ammonium acetate, 225 mlof ethanol and 70 ml of ether was stirred and heated under reflux for 18hrs. Most of the ether was removed under pressure to leave a biphasicmixture. The mixture was diluted with water and extracted withdichloromethane. The organic extract was dried over anhydrous magnesiumsulfate and the solvent was removed under pressure to yield 22.1 g ofproduct as an oily mixture of E- and Z-isomers. A 14.0 sample of the oilwas chromatographed on a Waters model 500 Preparative High PressureLiquid Chromatograph. Using (dichloromethane/methanol (4.0%) as theeluent, 3.5 g of starting material, 2.9 g (20.7%) of the less polaroxime (E-isomer) and 5.6 g (39.9%) of the more polar oxime (Z-isomer)were obtained. The less polar oxime (E-isomer) was recrystallized fromethyl acetate to give product as a solid, mp 151°-153°. Although thechromatographed oxime was essentially one isomer, uponrecrystallization, the compound isomerized, which resulted in a mixtureof E- and Z-isomers.

Analysis: Calculated for C₁₆ H₂₂ N₂ O₅ : 59.61%C, 6.88%H, 8.69%N. Found:59.33%C, 6.76%H, 8.65%N.

EXAMPLE 18 1-Acetyl-4-(5-fluoro-2-hydroxybenzoyl)piperidine oxime

A mixture of 12.7 g of1-acetyl-4-(5-fluoro-2-hydroxybenzoyl)-piperidine, 6.6 g ofhydroxylamine hydrochloride, 11.0 g of ammonium acetate and 200 ml ofethanol-ether was heated under reflux for 10 hrs. After cooling, most ofthe ethanol was removed under reduced pressure. The resultant suspensionwas diluted with water and extracted with dichloromethane. Thedichloromethane was evaporated in vacuo to give an oil. The oil wasdissolved in ethyl acetate and cyclohexane was added to precipitate asolid. The solid was recrystallized from ethyl acetate to give 8.8 g(65.4%) of product, mp, 181°-183°. The chromatogram showed 2 spots.

Analysis: Calculated for C₁₄ H₁₇ FN₂ O₃ : 59.99%C, 6.12%H, 10.00%N.Found: 59.82%C, 6.11%H, 9.89%N.

EXAMPLE 19 Z,1-Acetyl-4-(5-fluoro-2-hydroxybenzoyl)piperidineO-acetyloxime

A mixture of 197 g of 1-acetyl-4-(5-fluoro-2-hydroxybenzoyl)-piperidineoxime, 195 ml of acetic anhydride and 400 ml dichloromethane was stirredat ambient temperature for 16 hrs. A solid precipitated. The solid wascollected to give 127 g of product, predominantly as the Z isomer, mp,195°-197°. The dichloromethane filtrate was washed with water, aqueoussodium bicarbonate solution, dried over anhydrous magnesium sulfate andthe solvent removed in vacuo to give a solid. The solid was trituratedwith ether and collected to yield 47.8 g of product, predominantly the Eisomer. Total yield was 174.8 g (77.5%). A 4.0 g sample of the Z-richfraction was recrystallized from dimethylformamide to give 2.9 g ofZ-isomer, mp, 206°-208°.

Analysis: Calculated for C₁₆ H₁₈ FN₂ O₄ : 59.65%C, 5.94%H, 8.69%N.Found: 59.64%C, 6.03%H, 8.74%N.

EXAMPLE 20 1-Acetyl-4-(2,4-dichlorobenzoyl)piperidine oxime

A mixture of 13.0 g of 4-(2,4-dichlorobenzoyl)-N-acetylpiperidine, 6.8 gof hydroxylamine hydrochloride, 13.5 g of ammonium acetate, 127 ml ofethanol and 43 ml of water was stirred and heated at 130° for 24 hrs.The reaction mixture was evaporated and 1.3 l of water was added to theresidue. The water was decanted from the oil and the oil was dissolvedin about 150 ml dichloromethane. After washing with about 150 ml ofwater, drying over anhydrous magnesium sulfate and evaporating thesolvent, an oil was obtained, which after crystallization frommethanol/ether gave 4.25 g (31.1%) of product, mp 167°-168°.

Analysis: Calculated for C₁₄ H₁₆ Cl₂ N₂ O₂ : 53.36%C, 5.12%H, 8.89%N,22.50Cl. Found: 53.25%C, 5.14%H, 8.82%N, 22.22%Cl.

EXAMPLE 21 1-Formyl-4-(2,4-dichlorobenzoyl)piperidine oxime

a. To a stirred slurry of 125 g of aluminum chloride in 735 g of1,3-dichlorobenzene, was added 97 g of 1-formylisonipecotyl chloride.The mixture was heated to ca 70° and then at ca 120° for 2.5 hrs, withstirring. The unreacted dichlorobenzene was distilled in vacuum at 70°(16 mm). The residue was decomposed with 4 l of ice-water and 50 ml ofconc hydrochloric acid. After 17 hrs, the oil was separated bydecantation. The oil was washed twice with about 2 l of water anddissolved in 1 l of dichloromethane. The dichloromethane extract waswashed with 500 ml of 2 N sodium hydroxide, two times with 500 ml ofwater and dried over anhydrous magnesium sulfate. The dichloromethanewas distilled to yield 110 g (64%) of product as an oil.

b. A mixture of 105 g of 4-(2,4-dichlorobenzoyl)-1-formylpiperidine, 70g of hydroxylamine hydrochloride, 135.0 g of ammonium acetate, 1.05 l ofethanol and 350 ml of water was stirred and heated at 130° for 40 hrs.The reaction mixture was evaporated and 2 l of water was added to theresidue. The water was decanted from the oil and oil was washed twotimes with 500 ml water and then dissolved in about 400 mldichloromethane. The insoluble material was collected. Thedichloromethane extract was washed twice with 600 ml of water and theorganic extract was evaporated. Trituration with diisopropyl ether andcrystallization from acetone/ether gave 15.6 g (14.2%) of product, mp,149°-150°.

Analysis: Calculated for C₁₃ H₁₄ Cl₂ N₂ O₂ : 51.86%C, 4.86%H, 9.29%N.Found: 51.94%C, 4.86%H, 9/08%N.

EXAMPLE 22 4-(2,4-Dichlorobenzoyl)piperidine oxime hydrochloride

A mixture of 105 g of 4-(2,4-dichlorobenzoyl)-1-formylpiperidine, 70 gof hydroxylamine hydrochloride, 135 g of ammonium acetate, 1.05 l ofethanol and 350 ml of water was stirred and heated at 130° for 40 hrs.The reaction mixture was evaporated and 2.0 l of water was added to theresidue. The water was decanted from the oil and the oil was washed twotimes with 500 ml of water and dissolved in about 400 ml ofdichloromethane. The insoluble material was collected. Thedichloromethane extract was washed twice with 600 ml of water. Thecombined aqueous phases were made basic with potassium carbonate/water.The precipitate was filtered, washed with water and dried overphosphorus pentoxide in vacuo to yield 27.2 g (9.96%) of4-(2,4-dichlorobenzoyl)piperidine oxime. The insoluble material wasdissolved in hot water and made alkaline with potassium carbonate-water.The precipitate was filtered, washed with water and dried overphosphorus pentoxide in vacuo. The solid was dissolved in 200 mlmethanol and 2 ml of conc hydrochloric acid was added. After heating for5 mins, the solution was filtered and evaporated in vacuo to dryness.The residue was recrystallized from methanol-ether to yield product asthe hydrochloride, mp 284°.

Analysis: Calculated for C₁₂ H₁₅ C₁₂ N₂ O HCl: 46.53%C, 4.88%H, 9.05%N.Found: 46.75%C, 5.00%H, 8.97%N.

EXAMPLE 23 Z,4-(2-Hydroxy-4-methoxybenzoyl)-1-piperidine carboxylic acidphenylmethyl ester oxime

A solution of 39.0 g of 4-(2-hydroxy-3-methoxybenzoyl)-1-piperidinecarboxylic acid phenylmethyl ester, 10.9 g of hydroxylaminehydrochloride, 18.2 g of ammonium acetate, 600 ml/180 ml ofethanol/water was heated under reflux for 24 hrs. Most of the ethanolwas removed in vacuo to yield a biphasic mixture. The mixture wasextracted with dichloromethane. The dichloromethane extract was washedwith water, dried over anhydrous magnesium sulfate and the solvent wasremoved in vacuo to give an oil. The oil was dissolved in ether and asolid precipitated from solution. The solid was collected to give 19.9 g(49.3%) of product. The solid corresponded to one of the isomers.Removal of the filtrate gave an oil, which was rich in the other isomer.A 3.0 g sample of the solid was recrystallized from ethyl acetate-hexaneto yield 2.8 g of product as the Z-isomer, mp, 155°-156°.

Analysis: Calculated for C₂₁ H₂₄ N₂ O₅ : 65.60%C, 6.24%H, 7.29%N. Found:65.58%C, 6.26%H, 7.42%N.

EXAMPLE 24 1-Methyl-4-(2-fluorobenzoyl)piperidine oxime

A mixture of 5.2 g of 1-methyl-4-(2-fluorobenzoyl)piperidine, 2.5 g ofhydroxylamine hydrochloride, 5.4 g of ammonium acetate and 50+15 ml ofethanol-water was heated under reflux for 22 hrs. Most of the ethanolwas removed under reduced pressure. The aqueous mixture was made basicwith aqueous sodium hydroxide and the mixture was extracted withchloroform. The chloroform extract was dried over anhydrous magnesiumsulfate and the chloroform was evaporated in vacuo to give a solid. Thesolid was triturated with ether. Recrystallization from ethanol-watergave 3.0 g (52.6%) of product, mp, 136°-139°.

Analysis: Calculated for C₁₃ H₁₇ N₂ O: 66.08%C, 7.25%H, 11.86%N. Found:65.80%C, 7.21%H, 11.86%N.

EXAMPLE 25 4-(2,4-Difluorobenzoyl)-1-allylpiperidine oxime hydrochloride

A suspension of 4.80 g of 4-(2,4-difluorobenzoyl)piperidine oxime, 2.7 gof allyl bromide, 2.7 g of ammonium chloride and some crystals ofpotassium iodide in 50 ml of dimethylformamide was stirred undernitrogen at 85°-90° for 5 hrs. The reaction mixture was cooled, dilutedwith 30 ml of ethanol and added to 1000 ml of half saturated aqueoussodium chloride solution, prepared by diluting saturated sodium chloridesolution with an equal volume of water. After 16 hrs, the solid waswashed with water and dried. The solid was dissolved in 60 ml of ethanoland 1 ml of conc hydrochloric acid. After heating to 50°, the solventswere evaporated in vacuo. Recrystallization of the residue fromisopropanol-ether gave 2.63 g (43.5%) of product, mp, 239°.

Analysis: Calculated for C₁₅ H₁₈ F₂ N₂ O₁ HCl: 56.89%C, 6.04%H, 8.84%N.Found: 56.66%C, 5.90%H, 8.74%N.

EXAMPLE 26 3-(1-Methyl-4-piperidyl)-5-methyl-1,2-benzisoxazole fumarate

A solution of 50 g of 1-methyl-4-(2-chloro-5-methylbenzoyl)piperidine,32 g of hydroxylamine hydrochloride, 120 g of 85% potassium hydroxide,700 ml of ethoxyethanol and 700 ml of water was heated under reflux for10 hrs and then stirred at room temperature for 6 hrs. The reactionmixture was poured into 5 l of water and extracted with petroleum etherthree times. The extracts were washed with sodium chloride solution anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure to give 11 g (24%) of product as an oil. The fumaratesalt was made by dissolving 4.5 g of the benzisoxazole in 20 ml ofacetonitrile, containing 2.25 g of furmaric acid, and stirring for 2hrs. The precipitate was filtered and recrystallized three times fromethanol-ether to give analytical product, mp, 179.5°-180.5°.

Analysis: Calculated for C₁₄ H₁₈ N₂ O C₄ H₄ O₄ : 62.41%C, 6.40%H,8.09%N. Found: 62.23%C, 6.34%H, 8.08%N.

EXAMPLE 27 4-Fluoro-3-(1-methyl-4-piperidyl)-1,2-benzisoxazolehydrochloride

A stirred mixture of 209 g of1-methyl-4-(2,6-difluorobenzoyl)-piperidine, 400 g of potassiumhydroxide, 102 g of hydroxylamine hydrochloride, 2100 ml of isopropanoland 2100 ml of water was refluxed for 10 hrs and then stirred overnightat ambient temperature. The reaction mixture was poured into water andextracted with hexane. The hexane extracts were dried over anhydrousmagnesium sulfate, filtered and the solvent was removed in vacuo toyield a solid. The solid was purified by passing it through a silica gelcolumn (15:1) using 1% methanol in dichloromethane as eluent.Evaporation of the eluent provided a solid, which was dissolved inether. A hydrochloric acid-ether solution was added dropwise. Theprecipitate was collected and washed with ether to yield 24.71 g (14%)of product, mp, 221°-223°.

Analysis: Calculated for C₁₃ H₁₅ FN₂ O HCl: 57.90%C, 5.57%H, 10.39%N.Found: 57.79%C, 5.97%H, 10.13%N.

EXAMPLE 28 6-Methoxy-3-(1-acetyl-4-piperidyl)-1,2-benzisoxazole

a. A stirred mixture of 10.0 g of1-acetyl-4-(2-hydroxy-4-methoxybenzoyl)piperidine and 10 ml of aceticanhydride was heated to 60° for 10 mins and cooled to ambienttemperature to yield an oil. Hexane was added to the oil. The hexane wasdecanted and the oil was poured into water and extracted with ethylacetate. The ethyl acetate layer was washed with saturated sodiumbicarbonate solution, dried over anhydrous magnesium sulfate and thesolvent was removed in vacuo to yield 7.50 g of1-acetyl-4-(2-hydroxy-4-methoxybenzoyl)-piperidine o-acetyl oxime as anoil.

b. In a 3-neck round-bottom flask equipped with a mechanical stirrer anddropping funnel was added 1.20 g of a 50% sodium hydride oil dispersion.The sodium hydride was washed two times with anhydrous ethyl ether andthe supernate was removed with a pipette. A solution of 7.50 g of1-acetyl-4-(2-hydroxy-4-methoxy-benzoyl)piperidine o-acetyl oxime in 45ml of dimethylformamide was added dropwise while the reaction mixturewas stirred vigorously. The solution was stirred for 18 hrs at ambienttemperature and poured into water. The mixture was extracted with ethylacetate, dried over anhydrous magnesium sulfate and the solvent wasremoved in vacuo to yield an oil, which was triturated with petroleumether to yield 3.0 g of a solid. The solid was combined with 1.64 g ofpreviously prepared material and recrystallized 2 times from isopropylether to yield 2.80 g (29.5%) of product, mp, 91°-93°.

Analysis: Calculated for C₁₅ H₁₈ O₃ N₂ : 65.62%C, 6.56%H, 10.21%N.Found: 65.93%C, 6.63%H, 10.05%N.

EXAMPLE 29 4-(6-Methoxy-1,2-benzisoxazol-3-yl)-1-piperidine carboxylicacid phenylmethyl ester

a. A solution of 13.3 g of 4-(2-hydroxy-4-methoxybenzoyl)-1-piperidinecarboxylic acid phenylmethyl ester oxime (mostly of the E-configuration)and 3.6 ml of acetic anhydride in 70 ml of dichloromethane was stirredat ambient temperature for 16 hrs. Evaporation of the dichloromethanegave E, 4-(2-hydroxy-4-methoxybenzoyl-3-yl)-1-piperidine carboxylic acidphenylmethyl ester oxime acetate as an oil.

b. The acetate (16.4 g) was stirred and refluxed with 7.9 g of potassiumcarbonate and 30 ml of methanol for 2 hrs. The reaction mixture waspoured into water and the aqueous suspension extracted with ethylacetate. The ethyl acetate extract was washed with brine, dried overanhydrous magnesium sulfate and the ethyl acetate removed in vacuo toyield 13.2 g of an oil. The oil (8.7 g) was chromatographed on a WatersPrep 500 using two silica gel golumns and eluting withdichloromethane-methanol (1%). Two batches were isolated as solids, onecontaining the pure compound and the other slightly contaminated with amore polar material. The former batch was recrystallized from isopropylether and, after concentration of the mother liquor, yielded 2.1 g (38%)of product, mp 66°-68°.

Analysis: Calculated for C₂₁ H₂₂ N₂ O₄ : 68.83%C, 6.05%H, 7.64%N. Found:68.83%C, 5.98%H, 7.63%N.

EXAMPLE 30 5-Methoxy-3-(1-acetyl-4-piperidyl)-1,2-benzisoxazole

a. A mixture of 10.0 g ofE,1-acetyl-4-(2-hydroxy-5-methoxybenzoyl)piperidine E oxime and 4.5 mlof acetic anhydride was heated at 60° for 1.5 hrs. The resultant solidwas stirred with ether and collected to yield 7.0 g of theE,1-acetyl-4-(2-hydroxy-5-methoxybenzoyl)piperidine oxime acetate.

b. The 1-acetyl-4-(2-hydroxy-5-methoxybenzoyl)piperidine oxime acetate(7.0 g) was added slowly to a stirred suspension of 1.1 g ofether-washed sodium hydride (50% oil dispersion) in 80 ml ofdimethylformamide. The reaction was stirred at ambient temperature for16 hrs and then poured into 300 ml of water. The aqueous solution wasextracted 3× with 150 ml of ethyl acetate. The extracts were combined,washed with brine and water and dried over anhydrous magnesium sulfate.Evaporation of the ethyl acetate under reduced pressure yielded an oil.The oil crystallized upon trituration with ether to a solid. The solidwas recrystallized from toluene-cyclohexane and then from isopropylether to give 2.1 g (36.5%) of product, mp, 103°-105°.

Analysis: Calculated for C₁₅ H₁₈ N₂ O₃ : 65.67%C, 6.61%H, 10.21%N.Found: 65.76%C, 6.59%H, 10.31%N.

EXAMPLE 31 5,6-Dimethoxy-3-(1-acetyl-4-piperidyl-1,2-benzisoxazole

To a round-bottom flask equipped with a condenser was added 3.47 g of1-acetyl-4-(2-hydroxy-4,5-dimethoxybenzoyl)piperidine oxime acetate(predominately the E-isomer), 1.60 g of potassium carbonate and 30 ml ofmethanol. The mixture was stirred under reflux for 3.0 hrs and overnightat ambient temperature. The reaction mixture was poured into water. Thesolid was collected, washed well with water and recrystallized fromethyl acetate to yield 2.00 g (68.5%) of product, mp, 195°-197°.

Analysis: Calculated for C₁₆ H₂₀ N₂ O₄ : 63.12%C, 6.57%H, 9.21%N. Found:62.79%C, 6.66%H, 8.92%N.

EXAMPLE 32 3-(1-Acetyl-4-piperidyl)-5-fluoro-1,2-benzisoxazole

A 7.6 g sample of sodium hydride (50% oil dispersion) was washed withhexane and then suspended in 500 ml of dimethylformamide. The suspensionwas then stirred vigorously under nitrogen and 47.8 g of1-acetyl-4-(5-fluoro-2-hydroxybenzoyl)piperidine o-acetyl oxime (mostlyE-isomer) was added slowly. The reaction was stirred at ambienttemperature for 16 hrs and then poured into water. A solid separatedfrom solution. The solid was filtered and dried to give 21.6 g of theproduct, mp, 158°-160°. The filtrate was extracted with ethyl acetate.The extract was washed with water, dried over anhydrous magnesiumsulfate and evaporated. The residue was recrystallized from isopropylalcohol-water and from toluene-hexane to give an additional 2.9 g ofproduct, mp 158°-160°. Total yield was 63%.

Analysis: Calculated for C₁₄ H₁₅ F₂ N₂ O₂ : 64.11%C, 5.76%H, 10.68%N.Found: 64.18%C, 5.80%H, 10.58%N.

EXAMPLE 33 3-(1-Formyl-4-piperidyl)-6-chloro-1,2-benzisoxazole

a. To the mixed anhydride, prepared by dropping 40 ml of formic acid(98%), over 15 mins, into 80 ml of aceticanhydride at 20° (ice coolingnecessary), removing the ice-bath, allowing the temperature of themixture to warm to 55°-60° and, after 30 mins the mixture cooled to 15°,was added, over 5 mins, with stirring and cooling in an ice-bath, 15.0 gof 4-(2,4-dichlorobenzoyl)piperidine oxime. After stirring in an icebath for 6 hrs and stirring at 20° for 16 hrs, the mixed anhydride wasdistilled in vacuum using an oil bath (80°). The residue was washedtwice with 400 ml of water, dissolved in 200 ml of dichloromethane, andafter washing with 300 ml of water, the solvent was distilled in vacuo.Upon standing, the residue crystallized, yielding 15 g (90%) of1-formyl-4-(2,4-dichlorobenzoyl)piperidine oxime formate. A samplerecrystallized from dissopropylether-ether had, mp, 117°-177°.

b. To a stirred suspension of 1.25 g of sodium hydride (prepared from2.5 g 50% oil dispersion) in 100 ml of tetrahydrofuran was added, over20 mins, a solution of 10 g of1-formyl-4-(2,4-dichlorobenzoyl)piperidine O-formyl oxime in 60 ml ofdimethylformamide and 40 ml of tetrahydrofuran. The stirred mixture washeated to 80°-90° (oil bath temperature) for 5 hrs and after standing at20° for 16 hrs, 10 ml of methanol and 20 ml of water were added. Thereaction mixture was added to about 1.2 l of saturated sodium chloridesolution. The mixture was extracted with 400 ml of ether. The extractwas washed with 800 ml of water. The aqueous phase was extracted with400 ml of ether and the combined ether extracts were distilled to yieldan oil, which crystallized on standing. Recrystallization fromisopropanol-ether gave 6.5 g (67.2%) of product, mp, 114°- 115°.

Analysis: Calculated for C₁₃ H₁₃ ClN₂ O₂ : 58.98%C, 4.95%H, 10.59%N.Found: 58.71%C, 4.89%H, 10.47%N.

EXAMPLE 34 3-(1-Methyl-4-piperidyl)-1,2-benzisoxazole hydrochloride

To a solution of 28.2 g of 1-methyl-4-(2-fluorobenzoyl)piperidine and19.2 g of hydroxylamine in 400 ml of monethooxyethanol and 200 ml ofwater, was added 80.8 g of 85% potassium hydroxide dissolved in 200 mlof water. The solution was heated under reflux under nitrogen for 5hrs., cooled, poured into 1.5 l of water and the aqueous solution wasextracted with 3×400 ml of ether. The ether extracts were combined,washed with water, dried over anhydrous potassium carbonate and thesolvent removed in vacuo to give an oil. The oil was dissolved in etherand hydrogen chloride was added. The salt was dissolved in water,treated with aqueous sodium hydroxide solution and extracted withpetroleum ether (b.p. 30°-69°). The petroleum ether extract was driedover anhydrous potassium carbonate and the petroleum ether evaporated togive 16.9 of an oil. Treatment of the oil with hydrogen chloride inether and subsequent recrystallization from ethanol-ether gave 15.4 g(47%) of product, mp 250°-252°.

Analysis: Calculated for C₁₃ H₁₆ N₂ O HCl: 61.77%C, 6.38%H, 11.08%N.Found: 61.59%C, 6.66%H, 10.93%N.

EXAMPLE 35 3-(4-Piperidyl)-6-fluoro-1,2-benzisoxazole hydrochloride

A solution of 3.8 g of3-(1-formyl-4-piperidyl)-6-fluoro-1,2-benzisoxazole was dissolved in 45ml of ethanol (96%) and 45 ml of 3 N hydrochloric acid was heated underreflux for 3 hrs. The mixture was diluted with water to 500 ml, madealkaline with potassium carbonate solution and extracted withdichloromethane (5×200 ml). The combined extracts were washed withwater, dried over anhydrous magnesium sulfate and the dichloromethanewas removed in vacuo to give 3.7 g of an oil. The oil was dissolved in30 ml of methanol and 1 ml of concentrated hydrochloric acid was added.The methanol was distilled, 15 ml benzene was added and also distilled.The residue was treated with 100 ml of ether to give a solid. Tworecrystallizations from isopropanol-methanol-ether yielded 1.25 g(31.8%) of product, mp, 293°-295°.

Analysis: Calculated for C₁₂ H₁₃ FN₂ O HCl: 56.15%C, 5.49%H, 10.91%N.Found: 56.99%C, 5.66%H, 10.51%N.

EXAMPLE 36 5-Methoxy-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride

A mixture of 7.6 g of1-acetyl-5-methoxy-3-(4-piperidyl)-1,2-benzisoxazole and 45 ml of 6 Nhydrochloric acid was heated under reflux for 6 hrs. On standing for 8hrs, the solution deposited a solid which was filtered and dried toyield 3.2 g of product as the hydrochloride salt. The aqueous filtratewas made basic with 50% sodium hydroxide and the basic solution wasextracted with ether. The ether was removed in vacuo and the oil wasconverted with ether-hydrogen chloride to give 1.1 g of product as thehydrochloride salt. The combined salts were recrystallized three timesfrom methanol-ether to yield 1.7 g (23%) of product hydrochloride, mp,274°-277°.

Analysis: Calculated for C₁₃ H₁₆ N₂ O₂ HCl: 58.09%C, 6.38%H, 10.43%N.Found: 58.27%C, 6.49%H, 10.50%N.

EXAMPLE 37 5,6-Dimethoxy-3-(4-piperidyl)-1,2-benzisoxazole hydrobromide

A solution of 13.0 g of5,6-dimethoxy-3-(1-acetyl-4-piperidyl)-1,2-benzisoxazole and 80 ml of 6N hydrochloric acid was stirred under reflux for 6 hrs and overnight atambient temperature. The mixture was poured into water, basified with10% sodium hydroxide and extracted with ethylacetate. The extract weredried over anhydrous magnesium sulfate and the solvent was removed invacuo to yield a solid. The solid was dissolved in a minimum amount ofethanol-ether and the product as the hydrobromide salt was precipitatedwith a saturated hydrogen bromide-ether solution. The salt wasrecrystallized from ethanol-ether to yield 4.50 g of producthydrobromide, mp, 235°-237°.

Analysis: Calculated for C₁₄ H₁₈ N₂ O₃ HBr: 48.99%C, 5.25%H, 8.17%N.Found: 48.86%C, 5.48%H, 7.98%N.

EXAMPLE 38 5-Fluoro-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride

A mixture of 17.5 g of3-(1-acetyl-4-piperidyl)-5-fluoro-1,2-benzisoxazole and 110 ml of 6 Nhydrochloric acid was stirred under reflux for 6 hrs. After standing atambient temperature for ca 12 hrs, a solid was collected, washed withacetone and dried to yield 14.2 g (83%) of product as the hydrochloridesalt, mp 297°-299°.

Analysis: Calculated for C₁₂ H₁₃ FN₂ O HCl: 56.14%C, 5.50%H, 10.92%N.Found: 56.15%C, 5.41%H, 10.84%N.

EXAMPLE 39 6-Methoxy-3-(4-piperidyl)-1,2-benzisoxazole hydrobromide

To 30 ml of a saturated solution of hydrogen bromide and acetic acid wasadded, with stirring, 0.88 g of4-(6-methoxy-1,2-benzisoxazol-3-yl)-1-piperidine carboxylic acidphenylmethyl ester. The reaction was stirred at ambient temperature for55 min. The resultant solid was collected, washed with ether and driedto yield 0.5 g (79.8%) of product. Recrystallization from methanol gavethe analytical sample, mp 258°-260°.

Analysis: Calculated for C₁₃ H₁₆ N₂ O₂ HBr: 49.85%C, 5.47%H, 8.95%N.Found: 49.94%C, 5.41%H, 8.84%N.

EXAMPLE 40 3-(4-Piperidyl)-6-chloro-1,2-benzisoxazole hydrochloride

A solution of 19 g of3-(1-formyl-4-piperidyl)-6-chloro-1,2-benzisoxazole in 225 ml of ethanol(96%) and 225 ml of 3 N hydrochloric acid was heated under reflux for 3hrs. After 30 mins, the ethanol and the water were distilled in vacuo.Benzene (100 ml) was added and distilled. Recrystallization fromisopropanol-ether yielded 16.4 of salt. A 4 g sample was recrystallizedfrom ethanol-ether to give 3.55 g (74.2%) of product as thehydrochloride, mp, 228°-229°.

Analysis: Calculated for C₁₂ H₁₃ ClN₂ O HCl: 52.75%C, 5.16%H, 10.25%N.Found: 52.59%C, 5.13%H, 10.17%N.

EXAMPLE 41 4-(4-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidine carboxylicacid phenyl ester

A mixture of 1.74 g of4-fluoro-3-(1-methyl-4-piperidyl)-1,2-benzisoxazole, 1.25 g of potassiumcarbonate, 1.40 g of phenyl chloroformate and 50.0 ml of toluene wasstirred under reflux for 8.0 hrs. The mixture was poured into water andthe toluene layer was separated, dried over anhydrous magnesium sulfateand the solvent was removed in vacuo to yield an oil. The oil waspurified by passing through a silica gel column (20:1), using 1%methanol in dichloromethane as the eluent. The eluent was evaporated andthe residue solidified when scratched to yield a solid. The solid wasrecrystallized from petroleum-ether (bp 30°-60°) to yield 1.6 g (64%) ofproduct, mp 108°-110°.

Analysis: Calculated for C₁₉ H₁₇ FN₂ O₃ : 67.06%C, 5.00%H, 8.24%N.Found: 67.03%C, 5.20%H, 8.12%N.

EXAMPLE 42 5-Hydroxy-3-(4-piperidyl)-1,2-benzisoxazole hydrobromide

A mixture of 5.4 g of1-acetyl-5-methoxy-3-(4-piperidyl-1,2-benzisoxazole and 48% hydrogenbromide was heated under reflux for 10 hrs and the precipitate wascollected. Recrystallization from methanol-ether afforded 3.0 g (50.9%)of product hydrobromide, mp, 293°-295°.

Analysis: Calculated for C₁₂ H₁₄ N₂ O₂ HBr: 48.17%C, 5.05%H, 9.37%N.Found: 48.12%C, 5.00%H, 9.47%N.

EXAMPLE 43 4-(1,2-benzisoxazol-3-yl)-1-piperidine carboxylic acid phenylester

A mixture of 12.3 g of 3-(1-methyl-4-piperidyl)-1,2-benzisoxazolehydrochloride and aqueous sodium hydroxide was extracted into 200 ml oftoluene. The toluene solution was dried over anhydrous magnesiumsulfate, filtered and 8.8 g of phenyl chloroformate was added. Themixture was was heated under reflux under nitrogen for 16 hrs andcooled. The toluene was removed under reduced pressure and the resultantoil was taken up in ether. Petroleum ether (bp 30°-60°) was added andthe precipitate was collected to give 12.3 g (78%) of product, mp,96°-98°. Recrystallization of a sample from ethanol-water gave theanalytical sample, mp, 107°-109°.

Analysis: Calculated for C₁₉ H₁₈ N₂ O₃ : 70.79%C, 5.63%H, 8.69%N. Found:71.11%C, 5.69%H, 8.84%N.

EXAMPLE 44 3-(4-Piperidyl)-1,2-benzisoxazole hydrochloride

A mixture of 5.0 g of 4-(1,2-benzisoxazole-3-yl)-1-piperidine carboxylicacid phenyl ester, 100 ml of ethanol, 50 g of (85%) potassium hydroxideand 50 ml of water was heated under reflux, with stirring, undernitrogen for 16 hrs. Most of the ethanol was removed in vacuo and theresultant aqueous suspension was extracted with ether (3×50 ml). Theether extracts were combined, washed with water, dried over anhydrousmagnesium sulfate and the ether removed under reduced pressure to givean oil. The oil was dissolved in anhydrous ether and hydrogen chloridewas introduced to precipitate a 3.0 g of a hydrochloride salt.Recrystallization from methanol-ether gave 2.0 g (57%) of product as thehydrochloride, mp, 313°-315° (dec.).

Analysis: Calculated for C₁₂ H₁₄ N₂ O HCl: 60.37%C, 6.33%H, 11.74%N.Found: 60.52%C, 6.32%H, 11.67%N.

EXAMPLE 45 3-[1-(3-Dimethylaminopropyl)-4-piperidyl]-1,2-benzisoxazoledifumarate

A suspension of 3.5 g of 3-(4-piperidyl)-1,2-benzisoxazole, 2.3 g of3-dimethylaminopropyl chloride, 5.0 g of sodium bicarbonate and 3.0 g ofpotassium iodide in 100 ml of n-butanol was heated under reflux for 2hrs, cooled to room temperature and filtered. The filtrate was washedwith water and extracted with ether (3 times). The ether extract wasdried over anhydrous sodium sulfate and the solvent was removed underreduced pressure to give 3.9 g of oil. The oil was dissolved in 15 ml ofacetonitrile and 1.6 g of fumaric acid was added. The precipitate wasfiltered and recrystallized from methanol to give 2.2 (25%) of product,mp, 196°-197°.

Analysis: Calculated for C₁₇ H₂₅ N₃ O 2C₄ H₄ O₄ : 57.80%C, 6.48%H,8.09%N. Found: 57.73%C, 6.43%H, 7.98%N.

EXAMPLE 46 3-[1-(3-Diethylaminopropyl)-4-piperidyl]-1,2-benzisoxazoledifumarate

A suspension of 4.0 g of 3-(4-piperidyl)-1,2-benzisoxazole, 3.2 g of3-diethylaminopropyl chloride, 3.0 g of potassium iodide and 5.0 g ofsodium bicarbonate in 100 ml of butanol was heated under reflux for 2hrs, cooled to room temperature and filtered. The filitrate was washedwith water and extracted with ether (3 times). The ether extracts weredried over anhydrous sodium sulfate, filtered and evaporated to give anoil. The oil was dissolved in 10 ml of acetonitrile and 4.2 g of fumaricacid was added. The mixture was stirred for 2 hrs, filtered and thefilter cake was recrystallized three times from ethanol-ether to give2.8 g (26%) of product, mp 174°-176°.

Analysis: Calculated for C₁₉ H₂₉ N₃ O 2C₄ H₄ O₄ : 59.22%C, 6.81%H,7.67%N. Found: 59.26%C, 7.01%H, 7.33%N.

EXAMPLE 47 3-[1-(2-Dimethylaminoethyl)-4-piperidyl]-1,2-benzisoxazoledifumarate

A suspension of 4.5 g of 3-(4-piperidyl)-1,2-benzisoxazole, 2.6 g of2-dimethylaminoethyl chloride, 3.0 g of potassium iodide and 5.0 g ofpotassium carbonate in 100 ml of butanol was heated under reflux for 2hrs, cooled to room temperature and filtered. The filtrate was washedwith water and extracted with ether (3 times). The ether extracts weredried over anhydrous sodium sulfate and the solvent was removed underreduced pressure to give an oil. The soil was dissolved in 10 ml ofacetonitrile and 3.2 g of fumaric acid was added. The reaction mixturewas stirred for 2 hrs, filtered and the filter cake was recrystallizedthree times from ethanol-ether to give 2.2 g (19.8%) of product, mp,215°-217°.

Analysis: Calculated for C₁₉ H₂ 9_(N3) O 2C₄ H₄ O₄ : 57.02%C, 6.18%H,8.31%H. Found: 57.41%C, 6.21%H, 8.20%N.

EXAMPLE 48 3-[1-(2-Diethylaminoethyl)-4-piperidyl]-1,2-benzisoxazoledifumarate

A suspenson of 4.0 g of 3-(4-piperidyl)-1,2-benzisoxazole, 2.9 g of2-diethylaminoethyl chloride, 5.0 g of sodium bicarbonate and 3.0 g ofpotassium iodide in 100 ml of n-butanol was heated under reflux for 2hrs, cooled to room temperature and filtered. The butanol was removedunder reduced pressure and the residue was dissolved in ether, washedwith water and saturated sodium chloride, dried over anhydrous sodiumsulfate and the solvent was removed to give 3.0 g of an oil. The oil wasdissolved in 10 ml of acetonitrile and 2.2 g of fumaric acid was added.The suspension was stirred for 2 hrs. The precipitate was filtered andrecrystallized from ethanol-ether (4 times) to give 2.9 g (28.6%) ofproduct, mp, 192°-193.5°.

Analysis: Calculated for C₁₈ H₂₇ N₃ O 2C₄ H₄ O₄ : 58.53%C, 6.61%H,7.88%N. Found: 58.44%C, 6.68%H, 7.95%N.

EXAMPLE 49 3-(1-Allyl-4-piperidyl)-6-fluoro-1,2-benzisoxazolehydrochloride

A suspension of 4.95 g of 3-(4-piperidyl)-6-fluoro-1,2-benzisoxazole,3.0 g of allyl bromide, 3.0 g of potassium carbonate and some crystalsof potassium iodide in 70 ml of dimethylformamide was stirred undernitrogen at 85°-90° for 5 hrs. The reaction was cooled and added to 40ml ethanol. Half-saturated sodium chloride, prepared by adding an equalvolume of water to saturated sodium chloride solution was added. After16 hrs, the crystals were filtered, washed with water and dried,yielding 3.4 g of base. The base was dissolved in 60 ml of ethanol and1.5 ml conc hydrochloric acid. The mixture was heated to 50° and thesolvents were evaporated in vacuo. Benzene (60 ml) was added anddistilled off in vacuo, yielding a residue. The residue was trituratedwith ether, filtered and twice recrystallized from isopropanol-ether togive 2.4 g (59.3%) of product, mp, 198°.

Analysis: Calculated for C₁₅ H₁ 8_(F) ClN₂ O: 60.69%C, 6.11%H, 9.43%N.Found: 60.36%C, 6.15%H, 9.21%N.

EXAMPLE 50 3-(1-Allyl-4-piperidyl)-6-chloro-1,2-benzisoxazolehydrochloride

A suspension of 3.55 g of 3-(4-piperidyl)-6-chloro-1,2-benzisoxazole,2.0 g of allyl bromide, 2.0 g of potassium carbonate and some crystalsof potassium iodide in 47 ml of dimethylformamide was stirred undernitrogen at 85°-90° for 5 hrs. The reaction mixture was cooled andfiltered. The crystals were washed with dichloromethane. The combinedorganic solvents (dimethylformamide+dichloromethane) were distilled invacuo and to the residue was added with 30 ml ethanol and 500 mlhalf-saturated sodium chloride, prepared by diluting saturated sodiumchloride with an equal volume of water. After 16 hrs, the crystals werefiltered, washed with water and dried, yielding base. The base wasdissolved in 50 ml of ethanol and 1.2 ml of conc hydrochloric acid. Themixture was heated to 50°. The solvents were evaporated in vacuo.Benzene (60 ml) was added and distilled in vacuo. The residue wastriturated with ether, filtered and twice recrystallized fromisopropanol-ether, giving 3.0 g (63.9%) of product as the hydrochloride,mp, 178°-180°.

Analysis: Calculated for C₁₅ H₁₇ ClN₂ O: 57.54%C, 5.79%H, 8.94%N. Found:57.43%C, 5.69%H, 8.92%N.

EXAMPLE 51 3-(1-Allyl-4-piperidyl)-1,2-benzisoxazole hydrochloride

A suspension of 4.0 g of 3-(4-piperidyl)-1,2-benzisoxazole, 2.6 g ofallyl bromide, 5.0 g of bromide bicarbonate, and 3.0 g of potassiumiodide in 90 ml of dimethylformamide was stirred at 80° for 20 hrs. Thereaction was cooled, filtered and poured into 1 l of water. The mixturewas extracted with ether (three times) and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure to give an oil.The oil was dissolved in a small amount of ether into which hydrochloricacid was bubbled. The precipitate was recrystallized from ethanol-ether(three times) to give 2.4 g of product, mp, 174°-176°.

Analysis: Calculated for C₁₅ H₁₈ N₂ O HCl: 64.62%C, 6.87%H, 10.05%N.Found: 64.61%C, 6.87%H, 9.88%N.

EXAMPLE 52 3-(1-Cyclopropylmethyl-4-piperidyl)-1,2-benzisoxazolehydrochloride

To a suspension of 5.0 g of 3-(4-piperidyl)-1,2-benzisoxazole, 5.5 g ofsodium bicarbonate and 3.0 g of potassium iodide in 75 ml ofdimethylformamide was added, dropwise, 2.4 g of cyclopropylmethylchloride in 25 ml of dimethylformamide, with stirring. The reaction wasstirred at 80° for 20 hrs, cooled to room temperature and filtered. Thefiltrate was poured into 1 l of water and extracted with ether (threetimes). The ether extracts were washed with saturated sodium bicarbonatesolution, saturated sodium chloride solution and dried over anhydroussodium sulfate. The solvent was removed to give an oil, which wasdissolved in ether into which sodium chloride was bubbled. Theprecipitate was collected and recrystallized twice from ethanol to give3.5 g of product, mp, 234.5°-236°.

Analysis: Calculated for C₁₆ H₂₀ N₂ O HCl: 65.36%C, 7.23%H, 9.57%N.Found: 65.68%C, 7.30%H, 9.56%N.

EXAMPLE 53 3-[1-(β-Phenylethyl)-4-piperidyl]-1,2-benzisoxazolehydrochloride

To a suspension of 5.0 g of 3-(4-piperidyl)-1,2-benzisoxazole, 5.5 g ofsodium bicarbonate and 3.0 g of potassium iodide in 75 ml ofdimethylformamide at 60° was added dropwise 5.0 g of β-phenylethylbromide in 15 ml of dimethylformamide, with stirring. The reaction wasstirred at 60° for 20 hrs, cooled to room temperature and filtered. Thefiltrate was poured into 1 l of water and allowed to stand overnight.The solid was filtered, dried and dissolved in ether into whichhydrochloric acid was bubbled. The precipitate was recrystallized twicefrom ethanol to give 5.1 g (48%) of product, mp, 216°-217°.

Analysis: Calculated for C₂₀ H₂₂ N₂ O HCl: 70.06%C, 6.76%H, 8.17%N.Found: 70.01%C, 6.55%H, 8.22%N.

EXAMPLE 54 3-(1-Benzoyloxy-4-piperidyl)-1,2-benzisoxazole

A suspension of 5.0 g of 3-(4-piperidyl)-1,2-benzisoxazole, 6 g ofbenzoyl peroxide and 6.8 g of potassium carbonate in 100 ml of benzenewas stirred at room temperature for 18 hrs. The reaction was filteredand the solvent was removed under reduced pressure to give 7.5 g (97%)of product. A small amount was recrystallized once from acetone andthree times from ethanol to give the analytical sample, mp, 156°-158°.

Analysis: Calculated for C₁₉ H₁₈ N₂ O₃ : 70.79%C, 5.63%H, 8.69%N. Found:70.68%C, 5.62%H, 8.66%N.

EXAMPLE 55 3-(1-Hydroxy-4-piperidyl)-1,2-benzisoxazole hydrochloride

A solution of 4.1 g of 3-(1-benzoyloxy-4-piperidyl)-1,2-benzisoxazole,55 ml of ethanol and 35 ml of 10% sodium hydroxide solution was heatedunder reflux for 45 mins, cooled to room temperature and the ethanolremoved under reduced pressure. The residue was added to 50 ml of waterand the pH of the solution was adjusted to 6 with careful addition of 6N hydrochloric acid. The solution was extracted with chloroform. Thechloroform extracts were dried over anhydrous sodium sulfate and thesolvent was removed under reduced pressure. The residue was dissolved inether and a solution of ether-hydrochloric acid was added. Theprecipitate was collected and recrystallized from ethanol-ether (threetimes) to give 2.1 g (63%) of product, mp, 213°-216°.

Analysis: Calculated for C₁₂ H₁₄ N₂ O₂ HCl: 56.85%C, 5.94%H, 11.00%N,Found: 56.59%C, 6.01%H, 11.16%N.

EXAMPLE 56 6-Fluoro-3-(1-cyanomethyl-4-piperidyl)-1,2-benzisoxazole

A mixture of 3.1 g of 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazolehydrochloride, 4.9 g of potassium carbonate and 30 ml ofdimethylformamide was stirred at ambient temperature for 5 min.Potassium iodide (0.24 g) was added, followed by 0.76 ml ofchloroacetonitrile. The mixture was stirred and heated under nitrogen at80°-85° for 2 hrs and then poured into 300 ml of water. The solid wascollected and dried (vacuum oven). Recrystallization from ethanol-wateryielded 2.0 g (64%) of product. An analytical sample was obtained bycombining the 2.0 g sample with 0.8 g of another sample andrecrystallizing from ethanol-water to give 2.2 g of product, mp,126°-128°.

Analysis: Calculated for C₁₄ H₁₄ FN₃ O: 64.85%C, 5.44%H, 16.21%N. Found:64.86%C, 5.45%H, 16.07%N.

EXAMPLE 57 3-(1-Cyano-4-piperidyl)-5-methyl-1,2-benzisoxazole

A suspension of 0.5 g of3-(1-methyl-4-piperidyl)-5-methyl-1,2-benzisoxazole, 0.37 g of cyanogenbromide and 1.5 g of potassium carbonate in 50 ml of chloroform washeated under reflux for 48 hrs and stirred at room temperature for 48hrs. The reaction was filtered, the solvent was removed and the residuewas triturated with hexane to give a solid. The solid was recrystallizedfrom hexane (three times) to give 0.178 g (37%) of product, mp,125°-126°.

Analysis: Calculated for C₁₄ H₁₅ N₃ O: 69.69%C, 6.27%H, 17.41%N. Found:69.43% C, 6.19% H, 17.76% N.

EXAMPLE 58 3-(1-Cyano-4-piperidyl)-1,2-benzisoxazole

A suspension of 4.8 g of 3-(4-piperidyl)-1,2-benzisoxazole, 2.7 g ofcyanogen bromide, 5.0 g of sodium bicarbonate and 3.0 g of potassiumiodide in 100 ml of chloroform was heated under reflux overnight. Thereaction was cooled to room temperature, filtered and concentrated invacuo to give a solid. The benzisoxazole was purified on 120 g of silicagel, eluted with chloroform and recrystallized twice from acetone-hexaneto give 3.4 g (62.3%) of product, mp, 115°-117°.

Analysis: Calculated for C₁₃ H₁₃ N₃ O: 68.70%C, 5.77%H, 18.49%N. Found:68.58% C, 5.90% H, 18.38% N.

EXAMPLE 59 4-(2-Fluorobenzoyl)-1-methylpiperidine hydrochloride

To a suspension of 7.6 g of magnesium turnings in 25 ml oftetrahydrofuran was added a few drops of ethyl bromide, with stirringunder nitrogen. After the reaction began, approximately 50.0 g ofN-methyl-4-chloropiperidine in 125 ml of tetrahydrofuran was addeddropwise at a rate such as to maintain moderate reflux. The reactionmixture was heated under reflux an additional hr, and 37.2 g of2-fluorobenzonitrile in 50 ml of tetrahydrofuran was added dropwise.After completion of the addition, the reaction mixture was refluxed fortwo hrs, and stirred overnight at room temperature. The reaction mixturewas poured into a solution of 85 g of ammonium chloride in 1200 ml ofice water and heated on a steam bath for 3 hrs. The mixture was cooled,extracted with benzene (3×250 ml), dried over anhydrous sodium sulfate,and the excess solvent was removed under reduced pressure to give 62.72g (91%) of 4-(2-fluorobenzoyl)-1-methyl piperidine as an oil. A smallamount of 4-(2-fluorobenzoyl)-1-methyl piperidine (1.0 g) was removed,dissolved in ether and a solution of ethereal hydrochloric acid wasadded. The precipitate was collected, dried and recrystallized fromethanol-ether (2×) to give 0.5 g of 4-(2-fluorobenzoyl)-1-methylpiperidine hydrochloride, mp, 167°-169°.

Analysis: Calculated for C₁₃ H₁₇ ClFNO: 60.58%C, 6.65%H, 5.43%N, 7.37%F.Found: 60.30%C, 6.78%H, 5.43%N, 7.59%F.

EXAMPLE 60 3-(1-Formyl-4-piperidyl)-6-fluoro-1,2-benzisoxazole

To a stirring suspension of 1.34 g of sodium hydride (50% oil dispersionwashed two times with hexane and the hexane decanted) in 40 ml oftetrahydrofuran/dimethylformamide (3:1) was added, dropwise, 7.0 g of1-formyl-4-(2,4-difluorobenzoyl)piperidine oxime in 40 ml oftetrahydrofuran/dimethylformamide (3:1). The mixture was then stirred at90° for 3 hrs. Sodium hydride (0.77 g of 50% oil-dispersion treated asabove) was added. The mixture was stirred an additional hour at 90°. Theheater was removed. The following day the mixture was heated at 90° for5 hrs. An additional 0.5 g of sodium hydride (50% oil-dispersion treatedas above) was added. Heating and stirring were continued for 5 hrs. Thereaction mixture was cooled, poured into water, and the aqueoussuspension extracted with ether. (3 times, 250 ml). The ether extractswere combined, washed with brine and water and then dried over anhydrousmagnesium sulfate. Evaporation of the solvent gave an oil, which wastriturated with ether to give a solid. The filtrate was concentrated toan oil, which crystallized to a solid upon standing. The solid wastriturated with ether to give 1.0 g (15.4%) of product.

We claim:
 1. A compound of the formula ##STR18## wherein R is hydrogen,loweralkyl, loweralkenyl or a group of the formula ##STR19## wherein R¹is hydrogen, loweralkyl or a group of the formula OR² wherein R² isbenzyl; R³ is hydrogen or a group of the formula ##STR20## wherein R⁴ ishydrogen, loweralkyl; X is hydrogen, loweralkoxy, loweralkyl, halogen orhydroxy; Z is halogen or hydroxy; m is 1 or 2; the geometric isomers andoptical antipodes thereof; or salts thereof where R is hydrogen,loweralkyl or loweralkenyl.
 2. A compound of claim 1 wherein the oximegroup has the Z-configuration.
 3. A compound of claim 1 wherein theoxime group has the E-configuration.
 4. The compound of claim 1 which is4-(2,4-diflourobenzoyl-N-formylpiperidine O-oxime.
 5. The compound ofclaim 1 which is 1-acetyl-4-(2-hydroxy-5-methoxybenzoyl)piperidineoxime.
 6. The compound of claim 2 which isZ,1-acetyl-4-(4,5-dimethoxy-2-hydroxy)piperidine oxime.
 7. The compoundof claim 1 which is E,1-acetyl-4-(4,5-dimethoxy-2-hydroxy)piperidineoxime.
 8. The compound of claim 1 which is4-(2,4-dichlorobenzoyl)piperidine oxime.
 9. The compound of claim 1which is 4-(2,4-dichlorobenzoyl)-1-formylpiperidine oxime.
 10. Thecompound of claim 1 which isZ,4-(2-hydroxy-4-methoxybenzoyl)-1-piperidine carboxylic acidphenylmethyl ester oxime.
 11. The compound of claim 1 which is1-acetyl-4-(5-fluoro-2-hydroxybenzoyl)piperidine oxime.
 12. The compoundof claim 2 which is Z,1-acetyl-4-(5-fluoro-2-hydroxybenzoyl)piperidineO-acetyloxime.
 13. The compound of claim 3 which isE,1-acetyl-4-(5-fluoro-2-hydroxybenzoyl)piperidine O-acetyloxime. 14.The compound of claim 1 which is1-acetyl-4-(2,4-dichlorobenzoyl)piperidine oxime.
 15. The compound ofclaim 1 which is 4-(2,4-difluorobenzoyloxime)-n-allylpiperidine.
 16. Thecompound of claim 1 which is 1-formyl-4-(2,4-dichlorobenzoyl)piperidineoxime.
 17. The compound of claim 1 which is1-methyl-4-(2-chloro-5-methylbenzoyl)piperidine oxime.
 18. The compoundof claim 1 which is 1-methyl-4-(2,6-difluorobenzoyl)piperidine oxime.19. The compound of claim 1 which is1-acetyl-4-(2-hydroxy-4-methoxybenzoyl)piperidine O-acetyl oxime. 20.The compound of claim 1 which is4-(2-hydroxy-4-methoxybenzoyl)-1-piperidine carboxylic acid phenylmethyl ester O-acetyloxime.
 21. The compound of claim 1 which is1-acetyl-4-(2-hydroxy-5-methoxybenzoyl)piperidine oxime.
 22. Thecompound of the claim 1 which is 1-methyl-4-(2-fluorobenzoyl)piperidineoxime.